JP6533780B2 - Combination therapy comprising oxazolidinone-quinolones for use in the treatment of bacterial infections - Google Patents

Description

  Provided is a combination of at least one oxazolidinone-quinolone hybrid molecule and at least one further antibacterial compound, and its use as a medicament, in particular for the treatment or prevention of bacterial infections.

Combinations of antimicrobial agents have long been used to provide antimicrobial activity against multiple potential pathogens in the first-experience treatment of critically ill patients. There are three fundamental reasons to combine two or more antimicrobials:
1. Antimicrobial agents are combined to supplement their range or to enhance the activity of the antimicrobial agent by achieving synergy. Synergism is defined as the combined effect of two or more antimicrobials, which is significantly greater than that produced by combining each antimicrobial alone. However, additional, neutral or opposing effects also occur as a result of the combination of antimicrobial agents.
2. The dosage of either antimicrobial can be reduced to reduce toxicity.
3.2 The use of more than one antimicrobial may prevent or reduce the emergence of resistance to either antimicrobial when using a combination of antimicrobials. (Dowling HF, Finland M., Hamburger M., Jawetz E., Knight V., Lepper MH. H., Meiklejohn G., Rantz LA, Rhoads PS Clinical use in combination with antibiotics. AMA Arch Intern Med 1957; 99 (4): 536-538; The underlying reason for using a combination of Moellering RC antimicrobials Ann J Med 1983; 75 (2A): 4-8). In the era of increased drug resistance, particularly multidrug resistance, combined use of antimicrobials has progressed. Under these circumstances, achieving synergy is no longer the only result that combination therapy is required, as the clinical activity of the antimicrobial combination may be advantageous over the inactivity of each agent alone. Thus, acceptable results may result from the additive or even neutral activity of the combination. Acceptable results may also be obtained from the improved performance of the single active antimicrobial by other inactive agents, especially if the single active antimicrobial is less resistant. In this case it may be possible to prevent resistance to active antimicrobials.

  Because the antimicrobial results of susceptibility testing are usually obtained only after 24 to 72 hours, the initial treatment of infection becomes empirical and leading to clinical symptoms. Inappropriate initial treatment of infections in severe hospitalized patients has been shown to be accompanied by adverse consequences including increased morbidity and mortality and prolonged hospitalization. Thus, a common approach to antimicrobial treatment with first experience (especially in the treatment of difficult-to-treat pathogens) is to use a combination of antimicrobials to broaden the antimicrobial range. This is the case for community and hospital infections. (Leekha S., Terrell C. L., Edson R. S. General principles of antimicrobial treatment; Mayo Clin Proc. 2011; 86 (2): 156-167).

  Oxazolidinone-quinolone hybrids are compounds in which quinolones and oxazolidinone pharmacophores are linked together through a stable linker under physiological conditions. These compounds are useful antibacterial agents.

  Oxazolidinone-quinolone hybrid antibacterial agents and methods for their preparation are described, for example, in WO02059116, WO03002560, WO03031443, WO03032962, WO200505888, WO2005023801, WO2004096221, WO2007017828, WO2008056335, WO2008062379 and WO2009136379.

  It has now been found that the combination of the oxazolidinone-quinolone hybrid antibacterial agent with at least one further antibacterial compound results in an unexpected improvement of the antibacterial range and / or the antibacterial activity of the corresponding pharmaceutical composition.

The present invention provides the following combinations:
Provided is a combination of i) at least one (preferably one) oxazolidinone-quinolone hybrid and ii) at least one (preferably one) additional antibacterial compound different from the compound (i).
The invention further provides:
Provided is a pharmaceutical composition comprising i) at least one (preferably one) oxazolidinone-quinolone hybrid and ii) at least one (preferably one) further antibacterial compound different from the compound (i).

The invention further provides:
Provided is a kit of parts comprising at least one (preferably one) oxazolidinone-quinolone hybrid and ii) at least one (preferably one) further antibacterial compound different from the compound (i). .

  The combinations (eg, pharmaceutical compositions and / or kits of parts) of the invention can be used for the treatment and / or prevention of bacterial infections.

  Preferably, the at least one oxazolidinone-quinolone hybrid is selected from the compounds described in WO02059116, WO03002560, WO03031443, WO03032962, WO2005058888, WO2005023801, WO200409221, WO20070182828, WO2008056335, WO2008062379 and / or WO2009136379.

（式中、
Ａはアルキレン基、アルケニレン基、アルキニレン基、ヘテロアルキレン基、シクロアルキレン基、ヘテロシクロアルキレン基、アルキルシクロアルキレン基、ヘテロアルキルシクロアルキレン基、アリーレン基またはヘテロアリーレン基であり、これらの基はいずれも置換されていてもよく；
ＸはＣＲ⁷またはＮであり；
ＹはＣＲ⁶またはＮであり；
ｎは１、２または３であり；
ｍは１、２または３であり；
Ｒ¹はＨ、Ｆ、Ｃｌ、Ｂｒ、Ｉ、ＯＨ、ＮＨ₂、アルキル基またはヘテロアルキル基であり；
Ｒ²はＨ、ＦまたはＣｌであり；
Ｒ³はＨ、アルキル基、アルケニル基、アルキニル基、ヘテロアルキル基、シクロアルキル基、ヘテロシクロアルキル基、アルキルシクロアルキル基、ヘテロアルキルシクロアルキル基、アリール基、ヘテロアリール基、アラルキル基またはヘテロアラルキル基であり；これらの基はいずれも１、２またはそれ以上のＦもしくはＣｌのようなハロゲン原子またはアミノ基で置換されていてもよく；
Ｒ⁴は水素原子、式ＰＯ₃Ｒ⁹ ₂もしくはＰＯ₃Ｒ¹⁰の基または少なくとも１つのＯＨ、ＮＨ₂、ＳＯ₃Ｒ¹⁰、ＰＯ₃Ｒ⁹ ₂もしくはＣＯＯＨ基を有するヘテロアルキル基または天然のアミノ酸のエステルもしくはその誘導体であり、ここで、基Ｒ⁹は互いに独立して、Ｈ、アルキル、シクロアルキル、アリールまたはアラルキルであり、Ｒ¹⁰はＨ、アルキル、シクロアルキル、アリールまたはアラルキルであり；
Ｒ⁵は次の基：

から選択され、
Ｒ⁶はＨ、Ｆ、ＣｌまたはＯＭｅであり；
Ｒ⁷はＨ、Ｆ、Ｃｌ、ＯＨ、ＮＨ₂、置換もしくは非置換アルキル基または置換もしくは非置換ヘテロアルキル基であり、あるいは
Ｒ³がＨではなく、かつＲ⁷がＨ、Ｆ、ＯＨ、ＮＨ₂またはＣｌではない場合には、Ｒ³およびＲ⁷は、アルキレン、アルケニレンもしくはヘテロアルキレン基を介して結合していてもよく、またはシクロアルキレンもしくはヘテロシクロアルキレン基の一部であってもよく；
Ｒ⁸はＣ_1-6アルキル、Ｃ_1-6ヘテロアルキルまたはヘテロアラルキル基である） More preferably, the oxazolidinone-quinolone hybrid is a compound of formula (I) or a pharmaceutically acceptable salt, solvate or hydrate thereof.

(In the formula,
A represents an alkylene group, an alkenylene group, an alkynylene group, a heteroalkylene group, a cycloalkylene group, a heterocycloalkylene group, an alkylcycloalkylene group, a heteroalkylcycloalkylene group, an arylene group or a heteroarylene group, and all of these groups are May be substituted;
X is CR ⁷ or N;
Y is CR ⁶ or N;
n is 1, 2 or 3;
m is 1, 2 or 3;
R ¹ is H, F, Cl, Br, I, OH, NH ₂ , an alkyl group or a heteroalkyl group;
R ² is H, F or Cl;
R ³ is H, alkyl group, alkenyl group, alkynyl group, heteroalkyl group, cycloalkyl group, heterocycloalkyl group, alkylcycloalkyl group, heteroalkylcycloalkyl group, aryl group, heteroaryl group, aralkyl group or heteroaralkyl Any of these groups may be substituted with one, two or more halogen atoms such as F or Cl or an amino group;
R ⁴ is a hydrogen atom, a heteroalkyl group having a group of the formula PO ₃ R ⁹ ₂ or PO ₃ R ¹⁰ or at least one OH, NH ₂ , SO ₃ R ¹⁰ , PO ₃ R ⁹ ₂ or COOH group or a naturally occurring amino acid Esters or derivatives thereof, wherein the radicals R ⁹ are, independently of one another, H, alkyl, cycloalkyl, aryl or aralkyl, R ¹⁰ is H, alkyl, cycloalkyl, aryl or aralkyl;
R ⁵ is a group of:

Is selected from
R ⁶ is H, F, Cl or OMe;
R ⁷ is H, F, Cl, OH, NH ₂ , a substituted or unsubstituted alkyl group or a substituted or unsubstituted heteroalkyl group, or R ³ is not H and R ⁷ is H, F, OH, NH _{When not 2} or Cl, R ³ and R ⁷ may be linked via an alkylene, alkenylene or heteroalkylene group, or may be part of a cycloalkylene or heterocycloalkylene group;
R ⁸ is C _1-6 alkyl, C _1-6 heteroalkyl or heteroaralkyl group)

Alkyl is a linear or branched saturated hydrocarbon group and preferably contains 1 to 10, particularly preferably 1 to 6 carbon atoms, and examples thereof include methyl, ethyl, propyl, isopropyl, butyl and iso-. Butyl, sec-butyl, tert-butyl, n-pentyl, iso-pentyl, n-hexyl, 2,2-dimethylbutyl, n-octyl or n-pentyl group. Wherein the alkyl group, as defined, two or more substituents, for example F, Cl, Br, I, NH 2, OH, optionally substituted by SH or NO _2.

Alkenyl and alkynyl are linear or branched unsaturated hydrocarbon groups (having one, two or more double bonds and / or triple bonds, and alkenyl preferably has one or two double bonds. And alkynyl preferably has 1 or 2 triple bonds) and preferably contains 2 to 10, preferably 2 to 6 carbon atoms, and examples thereof include ethenyl (vinyl), propenyl (allyl) and iso. -Propenyl, n-pentenyl, butenyl, isoprenyl or hexa-2-enyl; ethynyl, propynyl or butynyl group. An alkenyl or alkynyl group as defined herein may be substituted by one, two or more substituents, such as F, Cl, Br, I, NH ₂ , OH, SH or NO ₂ .

A heteroalkyl group is an alkyl, alkenyl or alkynyl group as defined herein wherein one or more carbon atoms are replaced by an oxygen, nitrogen, phosphorus or sulfur atom, for example an alkoxy group such as methoxy, Ethoxy, propoxy, isopropoxy, butoxy or t-butoxy, alkoxyalkyl groups such as methoxymethyl, ethoxymethyl, 1-methoxyethyl, 1-ethoxyethyl, 2-methoxyethyl or 2-ethoxyethyl, alkylamino groups such as methyl Amino, ethylamino, propylamino, isopropylamino, dimethylamino or diethylamino, alkylthio groups such as methylthio, ethylthio or isopropylthio or cyano groups. It also refers to one of the above mentioned groups containing a keto group. Heteroalkyls are furthermore carboxylic acids or groups derived from carboxylic acid amides, such as acetyl, propionyl, acetyloxy, propionyloxy, acetylamino or propionylamino, carboxylalkyl groups, such as carboxymethyl, carboxyethyl or carboxypropyl, carboxyalkyl esters And an alkylthiocarboxyamino group, an alkoxyimino group, an alkylaminothiocarboxyamino group or an alkoxycarbonylamino group. Heteroalkyl groups as defined herein may be substituted by one, two or more substituents such as F, Cl, Br, I, NH ₂ , OH, SH or NO ₂ .

Cycloalkyl is a saturated or partially unsaturated (with one, two or more double bonds and / or triple bonds) cyclic group having one, two or more rings, and 3 to 14 It has a carbon ring atom, preferably 5 or 6 to 10 carbon ring atoms, and refers to, for example, a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetralin, cyclopentenyl or cyclohex-2-enyl group. Wherein the cycloalkyl group, as defined, two or more substituents, for example F, Cl, Br, I, OH, NH 2, SH, N 3, NO 2, alkyl groups such as methyl or ethyl , A heteroalkyl group such as methoxy, methylamino, dimethylamino or cyanide.

Heterocycloalkyl is defined herein in which one, two or more carbon ring atoms are replaced by one, two or more oxygen, nitrogen, phosphorus or sulfur atoms or an S (O) _1-2 group. A cycloalkyl such as piperidino, morpholino or piperazino.

  Alkylcycloalkyl is a group comprising a cycloalkyl according to the above definition and an alkyl, alkenyl or alkynyl group further according to the above definition, for example alkylcycloalkyl, cycloalkylalkyl, alkylcycloalkenyl, alkenylcycloalkyl And an alkynyl cycloalkyl group. The alkyl cycloalkyl group is preferably a cycloalkyl group comprising one or two rings having 3 to 10 (especially 3, 4, 5, 6 or 7) carbon ring atoms, and 1 or 2 to 6 Including one or two alkyl, alkenyl or alkynyl groups (especially alkyl groups) having carbon atoms.

  With heteroalkyl cycloalkyl groups, one or more (preferably 1, 2 or 3) carbon atoms are replaced by oxygen, nitrogen, silicon, selenium, phosphorus or sulfur atoms (preferably oxygen, sulfur or nitrogen atoms) And an alkyl cycloalkyl group as defined above. Heteroalkylcycloalkyl groups are preferably of 1 or 2 rings having 3 to 10 (especially 3, 4, 5, 6 or 7) ring atoms, and 1 or 2 to 6 carbon atoms. It contains one or two alkyl, alkenyl, alkynyl or heteroalkyl groups (especially alkyl or heteroalkyl groups). Examples of such groups are alkyl heterocycloalkyl, alkyl heterocycloalkenyl, alkenyl heterocycloalkyl, alkynyl heterocycloalkyl, heteroalkyl cycloalkyl, heteroalkyl heterocycloalkyl and heteroalkyl heterocycloalkenyl, and cyclic groups are It is saturated or mono-, di- or tri-unsaturated.

Aryl refers to an aromatic cyclic group having one, two or more rings with 5 to 14 carbon ring atoms, preferably 5 or 6 to 10 carbon ring atoms, such as phenyl or naphthyl groups. Here defined aryl group, two or more substituents, for example F, Cl, Br, I, OH, NH 2, SH, N 3, NO 2, alkyl groups such as methyl or ethyl, heteroalkyl It may be substituted by groups such as methoxy, methylamino, dimethylamino or cyanide.

  Heteroaryl is an aryl group as defined above which is substituted by oxygen, nitrogen, boron, phosphorus or sulfur atoms such as pyridyl, imidazolyl, pyrazolyl, quinolinyl, isoquinolinyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, 1,2,3-Triazolyl, 1,2,4 triazolyl, oxadiazolyl, thiadiazolyl, indolyl, indazolyl, tetrazolyl, pyrazinyl, pyrimidinyl and pyridazinyl groups.

  Aralkyl (or arylalkyl or alkylaryl) refers to groups which, in addition to aryl, contain both alkyl, alkenyl, alkynyl and / or cycloalkyl groups.

Heteroaralkyl (or heteroarylalkyl or heteroalkylaryl or heteroalkylheteroaryl etc.) means one, two, three or more oxygen atoms of 1, 2, 3 or more carbon atoms, nitrogen, phosphorus or sulfur atoms Or an aralkyl as defined above, substituted by a S (O) _1-2 group.

The expression “optionally substituted” is especially preferred in which one, two, three or more hydrogen atoms are replaced by fluorine, chlorine, bromine or iodine atoms or OH, = O, SH, SS, NH ₂ =. NH, refers to a group that is replaced by a N ₃ or NO ₂ group. This expression further, three or more unsubstituted C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 heteroalkyl, C _3-10 cycloalkyl, C _{2 -9} heterocycloalkyl, C _7-12 alkyl cycloalkyl, C _2-11 heteroalkyl cycloalkyl, C _6-10 aryl, C _1-9 heteroaryl, C _7-12 aralkyl or C _2-11 heteroaralkyl group It refers to a group which may be substituted.

  In preferred embodiments, all the alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, aralkyl and heteroaral groups described above may be substituted.

  In the present invention, the antibacterial agent, the antimicrobial agent and the antibacterial compound preferably have the same meaning.

Preferred compounds of formula (I) are those in which R ¹ is H.

Further preferred compounds of formula (I) are those in which R ² is F or H, particularly preferably R ² is F.

Even more preferred compounds of formula (I) are those wherein R ³ is ethyl, 2-propyl, C _3-6 cycloalkyl (ie cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl), phenyl or pyridyl group. Any of these groups may be substituted by 1, 2, 3 or more fluorine atoms or amino groups.

Further preferred compounds of formula (I) are those wherein R ³ is a cyclopropyl group.

Further preferred compounds of formula (I) are those wherein R ⁷ and R ³ are taken together to form the formula -O-CH ₂ -N (Me)-or -O-CH ₂ -CH (Me)-(especially -O-CH A bridge of _2- CH (Me)-) is formed. Here, the preferred stereochemical structure at the chiral center is that which results in the (S) configuration in the final compound.

Even more preferred compounds of formula (I) are those in which R ⁴ is hydrogen or a group of the formula SO ₃ H, PO ₃ H ₂ , CH ₂ OCPO ₃ H ₂ or COCH ₂ CH ₂ COOH.

Further preferred compounds of formula (I) are esters of amino acids in which R ⁴ is natural or derivatives thereof (for example, a group of formula —COCHR′NH ₂ or derivatives such as esters, amides or alkylamines thereof, wherein R ′ Is the side chain of a naturally occurring amino acid such as aspartic acid, glutaric acid, lysine etc.), eg dimethylaminoglycine OCOCH ₂ N (CH ₃ ) ₂ ).

Particularly preferred compounds of formula (I) are those in which R ⁴ is hydrogen or a group of the formula PO ₃ H ₂ .

を有する。 Further preferred compounds of formula (I) are those wherein R ⁵ is

Have.

を有する。 Particularly preferred compounds of formula (I) are those wherein R ⁵ is

Have.

Further preferred compounds of formula (I) are those wherein R ⁸ is a C _1-6 alkyl or C _1-6 heteroalkyl group.

Even more preferred compounds of formula (I) are those wherein R ⁸ is of the formula -CH ₂ NHCOCH = CH aryl, CH ₂ O heteroaryl (especially -oxa-3-oxazole), -CH ₂ NHSO ₂ Me, -CH ₂ NHCOOMe, -CH ₂ NHCOMe, is _{-CH 2 OH, -CH 2 NHCS 2} Me, -CH 2 NHCSMe, -CH 2 NHCSNH 2, -CH 2 NHCSOMe or -NHCOMe, especially -CH ₂ OH or -CH ₂ NHCOMe groups .

を有する。 Particularly preferred compounds of formula (I) are those wherein R ⁵ is

Have.

Even more preferred compounds of formula (I) are those wherein R ⁷ is H, F, Cl or a methoxy group which may be substituted by one, two or three fluorine atoms.

Particularly preferred compounds of formula (I) are those in which R ⁷ is H or a methoxy group.

  Further preferred compounds of formula (I) are those in which X is N or CH, particularly preferably X is CH.

  Even more preferred compounds of formula (I) are those wherein Y is CH.

  Further preferred compounds of formula (I) are those in which n is 1 or 2.

  Even more preferred compounds of formula (I) have m = 2.

  Particularly preferred compounds of formula (I) are those in which n is 2 and m is 2.

Further preferred compounds of formula (I) are those wherein A is C _1-6 alkylene, C _2-6 alkenylene, C _2-6 alkynylene, C _1-6 heteroalkylene, cyclopropylene, epoxide, aziridine, thioepoxide, lactam or lactone And any of these groups may be substituted.

Further preferred compounds of formula (I) are those wherein A is a group of the formula -O-B-, wherein oxygen is attached to a phenyl or pyridyl group and B is one, two or more hydroxy or amino groups And a C _1-4 alkylene group, a C _2-4 alkenylene group, a C _2-4 alkynylene group or a C _1-4 heteroalkylene group which may be substituted by

Particularly preferred compounds of formula (I), A has the formula _{-CH 2 CH 2 -, - OCH} 2 -, - OCH 2 CH 2 -, - SCH 2 -, - SCH 2 CH 2 -, - CH≡CH-, It is a group of -CCHC-, -CH (OH) CH (OH)-or -CH (NH ₂ ) CH (OH)-.

Particularly preferred compounds of formula (I) are those in which B is CH ₂ or CH ₂ CH ₂ .

（式中、残基は上で定義した通りである） Particularly preferred oxazolidinone-quinolone hybrids are compounds of formula (II) or a pharmaceutically acceptable salt, solvate or hydrate thereof.

(Wherein the residue is as defined above)

In preferred embodiments, B is CH ₂ or CH ₂ CH ₂ ; X is CH, N or C-OMe, R ³ is cyclopropyl, or X is CR ⁷ and R ⁷ And R ³ together form a bridge of the formula —O—CH ₂ —CH (Me) —, wherein the stereochemistry of the preferred chiral centers results in the (S) configuration in the final compound N is 1, 2 or 3 (preferably 2), m is 2 and R ⁴ is hydrogen or a group of the formula PO ₃ H ₂ .

Further preferred is the mono-, di- or trisodium salt (most preferably a monosodium salt) of a compound of formula (I) or (II) or mixtures thereof. Particularly preferred are mono-, di- or trisodium salts (most preferably monosodium salts) or mixtures thereof of compounds of formula (I) or (II), wherein R ⁴ is PO ₃ H ₂ .

Particularly preferred is that R ³ is a cyclopropyl group, X is CH or N, n is 2 and m is 2 and R ⁴ is PO ₃ H ₂ and B is CH ₂ It is the monosodium salt of the compound of formula (II).

  Certain compounds of formula (I) or (II) described herein may be tautomers, various geometric isomers (usually cis / trans isomers or more generally) which may specifically mention only one. Having different optical isomers (usually named as Kern Ingold Prelog or R / S system) as a result of (E) and (Z) isomers) or one or more chiral carbon atoms Should be understood. In addition, some compounds may be shown as polymorphs. All these tautomers, geometric or optical isomers (as well as racemates and diastereomers) and polymorphs are included in the present invention.

７−（４−｛４−［（５Ｓ）−５−（アセチルアミノ−メチル）−２−オキソ−オキサゾリジン−３−イル］−２−フルオロ−フェノキシメチル｝−４−ホスホノオキシ−ピペリジン−１−イル）−１−シクロプロピル−６−フルオロ−４−オキソ−１，４−ジヒドロ−［１，８］ナフチリジン−３−カルボン酸：

７−（４−｛４−［（５Ｓ）−５−（アセチルアミノ−メチル）−２−オキソ−オキサゾリジン−３−イル］−２−フルオロ−フェノキシメチル｝−４−（２，６−ジアミノ−ヘキサノイルオキシ）−ピペリジン−１−イル）−１−シクロプロピル−６−フルオロ−４−オキソ−１，４−ジヒドロ−［１，８］ナフチリジン−３−カルボン酸：

コハク酸モノ−（４−｛４−［（５Ｓ）−５−（アセチルアミノ−メチル）−２−オキソ−オキサゾリジン−３−イル］−２−フルオロ−フェノキシメチル｝−１‐（６−カルボキシ−８−シクロプロピル−３−フルオロ−４−オキソ−５，８−ジヒドロ−［１，８］ナフチリジン−２−イル）−ピペリジン−４−イル）エステル：

７−（４−｛４−［（５Ｓ）−５−（アセチルアミノ−メチル）−２−オキソ−オキサゾリジン−３−イル］−２−フルオロ−フェノキシメチル｝−４−ヒドロキシ−ピペリジン−１−イル）−１−シクロプロピル−６−フルオロ−４−オキソ−１，４−ジヒドロ−キノリン−３−カルボン酸：

７−（４−｛４−［（５Ｓ）−５−（アセチルアミノ−メチル）−２−オキソ−オキサゾリジン−３−イル］−２−フルオロ−フェノキシメチル｝−４−ホスホノオキシ−ピペリジン−１−イル）−１−シクロプロピル−６−フルオロ−４−オキソ−１，４−ジヒドロ−キノリン−３−カルボン酸：

７−（４−｛４−［（５Ｓ）−５−（アセチルアミノ−メチル）−２−オキソ−オキサゾリジン−３−イル］−２−フルオロ−フェノキシメチル｝−４−ヒドロキシ−ピペリジン−１−イル）−１−シクロプロピル−６−フルオロ−８−メトキシ−４−オキソ−１，４−ジヒドロ−キノリン−３−カルボン酸：

７−（４−｛４−［（５Ｓ）−５−（アセチルアミノ−メチル）−２−オキソ−オキサゾリジン−３−イル］−２−フルオロ−フェノキシメチル｝−４−ヒドロキシ−ピペリジン−１−イル）−１−シクロプロピル−８−メトキシ−４−オキソ−１，４−ジヒドロ−キノリン−３−カルボン酸：

９−（４−｛４−［（５Ｓ）−５−（アセチルアミノ−メチル）−２−オキソ−オキサゾリジン−３−イル］−２−フルオロ−フェノキシメチル｝−４−ヒドロキシ−ピペリジン−１−イル）−８−フルオロ−３−メチル−６−オキソ−２，３−ジヒドロ−６Ｈ−１−オキサ−３ａ−アザ−フェナレン−５−カルボン酸：

７−（３−｛４−［（５Ｓ）−５−（アセチルアミノ−メチル）−２−オキソ−オキサゾリジン−３−イル］−２−フルオロ−フェノキシメチル｝−３−ヒドロキシ−ピロリジン−１−イル）−１−シクロプロピル−６−フルオロ−４−オキソ−１，４−ジヒドロ−［１，８］ナフチリジン−３−カルボン酸：

７−（３−｛４−［（５Ｓ）−５−（アセチルアミノ−メチル）−２−オキソ−オキサゾリジン−３−イル］−２−フルオロ−フェノキシメチル｝−３−ヒドロキシ−ピロリジン−１−イル）−１−シクロプロピル−６−フルオロ−４−オキソ−１，４−ジヒドロ−キノリン−３−カルボン酸：

７−（３−｛４−［（５Ｓ）−５−（アセチルアミノ−メチル）−２−オキソ−オキサゾリジン−３−イル］−２−フルオロ−フェノキシメチル｝−３−ヒドロキシ−ピロリジン−１−イル）−１−シクロプロピル−６−フルオロ−８−メトキシ−４−オキソ−１，４−ジヒドロ−キノリン−３−カルボン酸：

７−（３−｛４−［（５Ｓ）−５−（アセチルアミノ−メチル）−２−オキソ−オキサゾリジン−３−イル］−２−フルオロ−フェノキシメチル｝−３−ヒドロキシ−ピロリジン−１−イル）−１−シクロプロピル−８−メトキシ−４−オキソ−１，４−ジヒドロ−キノリン−３−カルボン酸：

９−（３−｛４−［（５Ｓ）−５−（アセチルアミノ−メチル）−２−オキソ−オキサゾリジン−３−イル］−２−フルオロ−フェノキシメチル｝−３−ヒドロキシ−ピロリジン−１−イル）−８−フルオロ−３−メチル−６−オキソ−２，３−ジヒドロ−６Ｈ−１−オキサ−３ａ−アザ−フェナレン−５−カルボン酸：

７−（４−｛４−［（５Ｓ）−５−（アセチルアミノ−メチル）−２−オキソ−オキサゾリジン−３−イル］−２−フルオロ−フェノキシメチル｝−４−ヒドロキシ−アゼパン−１−イル）−１−シクロプロピル−６−フルオロ−４−オキソ−１，４−ジヒドロ−キノリン−３−カルボン酸：

７−（４−｛４−［（５Ｓ）−５−（アセチルアミノ−メチル）−２−オキソ−オキサゾリジン−３−イル］−２−フルオロ−フェノキシメチル｝−４−ヒドロキシ−アゼパン−１−イル）−１−シクロプロピル−６−フルオロ−４−オキソ−１，４−ジヒドロ−［１，８］ナフチリジン−３−カルボン酸：

７−（４−｛４−［（５Ｓ）−（アセチルアミノ−メチル）−２−オキソ−オキサゾリジン−３−イル］−２−フルオロ−フェノキシメチル｝−４−ホスホノオキシ−ピペリジン−１−イル）−１−シクロプロピル−６−フルオロ−４−オキソ−１，４−ジヒドロ−キノリン−３−カルボン酸のナトリウム塩：

７−（４−｛４−［（５Ｓ）−（アセチルアミノ−メチル）−２−オキソ−オキサゾリジン−３−イル］−２−フルオロ−フェニルエチニル｝−４−ヒドロキシ−ピペリジン−１−イル）−１−シクロプロピル−６−フルオロ−４−オキソ−１，４−ジヒドロ−キノリン−３−カルボン酸：

７−（４−｛４−［（５Ｓ）−（アセチルアミノ−メチル）−２−オキソ−オキサゾリジン−３−イル］−２−フルオロ−フェニルエチニル｝−４−ヒドロキシ−ピペリジン−１−イル）−１−シクロプロピル−６−フルオロ−４−オキソ−１，４−ジヒドロ−［１，８］ナフチリジン−３−カルボン酸：

７−［４−（２−｛４−［（５Ｓ）−（アセチルアミノ−メチル）−２−オキソ−オキサゾリジン−３−イル］−２−フルオロ−フェニル｝−エチル）−４−ヒドロキシ−ピペリジン−１−イル）−１−シクロプロピル−６−フルオロ−４−オキソ−１，４−ジヒドロ−キノリン−３−カルボン酸：

および
１−シクロプロピル−６−フルオロ−７−［４−（｛２−フルオロ−４−［（５Ｒ）−５−（ヒドロキシメチル）−２−オキソ−１，３−オキサゾリジン−３−イル］フェノキシ｝メチル）‐４−ヒドロキシピペリジン−１−イル］−４−オキソ−１，４−ジヒドロキノリン−３−カルボン酸： Particularly preferred examples of the compounds of the formula (I) or (II) are the compounds described below or their pharmacologically acceptable salts, solvates or hydrates.
7- (4- {4-[(5S) -5- (Acetylamino-methyl) -2-oxo-oxazolidin-3-yl] -2-fluoro-phenoxymethyl} -4-hydroxy-piperidin-1-yl ) -1-Cyclopropyl-6-fluoro-4-oxo-1,4-dihydro- [1,8] naphthyridine-3-carboxylic acid:

7- (4- {4-[(5S) -5- (Acetylamino-methyl) -2-oxo-oxazolidin-3-yl] -2-fluoro-phenoxymethyl} -4-phosphonoxy-piperidin-1-yl ) -1-Cyclopropyl-6-fluoro-4-oxo-1,4-dihydro- [1,8] naphthyridine-3-carboxylic acid:

7- (4- {4-[(5S) -5- (Acetylamino-methyl) -2-oxo-oxazolidin-3-yl] -2-fluoro-phenoxymethyl} -4- (2,6-diamino- Hexanoyloxy) -piperidin-1-yl) -1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro- [1,8] naphthyridine-3-carboxylic acid:

Succinic acid mono- (4- {4-[(5S) -5- (acetylamino-methyl) -2-oxo-oxazolidin-3-yl] -2-fluoro-phenoxymethyl} -1- (6-carboxy- 8-Cyclopropyl-3-fluoro-4-oxo-5,8-dihydro- [1,8] naphthyridin-2-yl) -piperidin-4-yl) ester:

7- (4- {4-[(5S) -5- (Acetylamino-methyl) -2-oxo-oxazolidin-3-yl] -2-fluoro-phenoxymethyl} -4-hydroxy-piperidin-1-yl ) -1-Cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid:

7- (4- {4-[(5S) -5- (Acetylamino-methyl) -2-oxo-oxazolidin-3-yl] -2-fluoro-phenoxymethyl} -4-phosphonoxy-piperidin-1-yl ) -1-Cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid:

7- (4- {4-[(5S) -5- (Acetylamino-methyl) -2-oxo-oxazolidin-3-yl] -2-fluoro-phenoxymethyl} -4-hydroxy-piperidin-1-yl ) -1-Cyclopropyl-6-fluoro-8-methoxy-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid:

7- (4- {4-[(5S) -5- (Acetylamino-methyl) -2-oxo-oxazolidin-3-yl] -2-fluoro-phenoxymethyl} -4-hydroxy-piperidin-1-yl ) -1-Cyclopropyl-8-methoxy-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid:

9- (4- {4-[(5S) -5- (Acetylamino-methyl) -2-oxo-oxazolidin-3-yl] -2-fluoro-phenoxymethyl} -4-hydroxy-piperidin-1-yl ) -8-Fluoro-3-methyl-6-oxo-2,3-dihydro-6H-1-oxa-3a-aza-phenalene-5-carboxylic acid:

7- (3- {4-[(5S) -5- (Acetylamino-methyl) -2-oxo-oxazolidin-3-yl] -2-fluoro-phenoxymethyl} -3-hydroxy-pyrrolidin-1-yl ) -1-Cyclopropyl-6-fluoro-4-oxo-1,4-dihydro- [1,8] naphthyridine-3-carboxylic acid:

7- (3- {4-[(5S) -5- (Acetylamino-methyl) -2-oxo-oxazolidin-3-yl] -2-fluoro-phenoxymethyl} -3-hydroxy-pyrrolidin-1-yl ) -1-Cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid:

7- (3- {4-[(5S) -5- (Acetylamino-methyl) -2-oxo-oxazolidin-3-yl] -2-fluoro-phenoxymethyl} -3-hydroxy-pyrrolidin-1-yl ) -1-Cyclopropyl-6-fluoro-8-methoxy-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid:

7- (3- {4-[(5S) -5- (Acetylamino-methyl) -2-oxo-oxazolidin-3-yl] -2-fluoro-phenoxymethyl} -3-hydroxy-pyrrolidin-1-yl ) -1-Cyclopropyl-8-methoxy-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid:

9- (3- {4-[(5S) -5- (Acetylamino-methyl) -2-oxo-oxazolidin-3-yl] -2-fluoro-phenoxymethyl} -3-hydroxy-pyrrolidin-1-yl ) -8-Fluoro-3-methyl-6-oxo-2,3-dihydro-6H-1-oxa-3a-aza-phenalene-5-carboxylic acid:

7- (4- {4-[(5S) -5- (Acetylamino-methyl) -2-oxo-oxazolidin-3-yl] -2-fluoro-phenoxymethyl} -4-hydroxy-azepan-1-yl ) -1-Cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid:

7- (4- {4-[(5S) -5- (Acetylamino-methyl) -2-oxo-oxazolidin-3-yl] -2-fluoro-phenoxymethyl} -4-hydroxy-azepan-1-yl ) -1-Cyclopropyl-6-fluoro-4-oxo-1,4-dihydro- [1,8] naphthyridine-3-carboxylic acid:

7- (4- {4-[(5S)-(Acetylamino-methyl) -2-oxo-oxazolidin-3-yl] -2-fluoro-phenoxymethyl} -4-phosphonoxy-piperidin-1-yl)- Sodium salt of 1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid:

7- (4- {4-[(5S)-(Acetylamino-methyl) -2-oxo-oxazolidin-3-yl] -2-fluoro-phenylethynyl} -4-hydroxy-piperidin-1-yl)- 1-Cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid:

7- (4- {4-[(5S)-(Acetylamino-methyl) -2-oxo-oxazolidin-3-yl] -2-fluoro-phenylethynyl} -4-hydroxy-piperidin-1-yl)- 1-Cyclopropyl-6-fluoro-4-oxo-1,4-dihydro- [1,8] naphthyridine-3-carboxylic acid:

7- [4- (2- {4-[(5S)-(Acetylamino-methyl) -2-oxo-oxazolidin-3-yl] -2-fluoro-phenyl} -ethyl) -4-hydroxy-piperidine- 1-yl) -1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid:

And 1-cyclopropyl-6-fluoro-7- [4-({2-fluoro-4-[(5R) -5- (hydroxymethyl) -2-oxo-1,3-oxazolidin-3-yl] phenoxy] } Methyl) -4-hydroxypiperidin-1-yl] -4-oxo-1,4-dihydroquinoline-3-carboxylic acid:

および
７−（４−｛４−［（５Ｓ）−５−（アセチルアミノ−メチル）−２−オキソ−オキサゾリジン−３−イル］−２−フルオロ−フェノキシメチル｝−４−ホスホノオキシ−ピペリジン−１−イル）−１−シクロプロピル−６−フルオロ−４−オキソ−１，４−ジヒドロ−キノリン−３−カルボン酸：

またはその塩、例えば７−（４−｛４−［（５Ｓ）−５−（アセチルアミノ−メチル）−２−オキソ−オキサゾリジン−３−イル］−２−フルオロ−フェノキシメチル｝−４−ホスホノオキシ−ピペリジン−１−イル）−１−シクロプロピル−６−フルオロ−４−オキソ−１，４−ジヒドロ−キノリン−３−カルボン酸のナトリウム塩。 Particularly preferably, at least one oxazolidinone-quinolone hybrid is selected from the following compounds:
7- (4- {4-[(5S) -5- (Acetylamino-methyl) -2-oxo-oxazolidin-3-yl] -2-fluoro-phenoxymethyl} -4-hydroxy-piperidin-1-yl ) -1-Cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid:

And 7- (4- {4-[(5S) -5- (acetylamino-methyl) -2-oxo-oxazolidin-3-yl] -2-fluoro-phenoxymethyl} -4-phosphonoxy-piperidine-1-) Yl) -1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid:

Or a salt thereof, such as 7- (4- {4-[(5S) -5- (acetylamino-methyl) -2-oxo-oxazolidin-3-yl] -2-fluoro-phenoxymethyl} -4-phosphonoxy- Piperidine-1-yl) -1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid sodium salt.

  7- (4- {4-[(5S) -5- (Acetylamino-methyl) -2-oxo-oxazolidin-3-yl] -2-fluoro-phenoxymethyl} -4-phosphonoxy-piperidin-1-yl ) 1-Cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid and its salts are active agents 7- (4- {4-[(5S) -5- (acetyl) Amino-methyl) -2-oxo-oxazolidin-3-yl] -2-fluoro-phenoxymethyl} -4-hydroxy-piperidin-1-yl) -1-cyclopropyl-6-fluoro-4-oxo-1, It is a prodrug of 4-dihydro-quinoline-3-carboxylic acid.

  7- (4- {4-[(5S) -5- (Acetylamino-methyl) -2-oxo-oxazolidin-3-yl]-when administered intravenously to some animal species, especially mice and rats. 2-Fluoro-phenoxymethyl} -4-phosphonoxy-piperidin-1-yl) -1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid sodium salt (Compound 1 The active substance 7- (4- {4-[(5S) -5- (acetylamino-methyl) -2-oxo-oxazolidin-3-yl] -2-fluoro-phenoxymethyl} -4-hydroxy-piperidine) -1-yl) -1-Cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid (compound 2) was rapidly converted. The very good solubility in aqueous media allows one to easily formulate (compound 1) using lyophilisation. Compound 1 may be formulated, for example, with sorbitol and sodium hydroxide and lyophilized in a glass vial to improve the stability of the lyophilizate and reduce the reconstitution time. The lyophilizate can be easily reconstituted by adding water for injection and gently shaking to form a sterile yellow solution ready for intravenous injection.

Preferably, the at least one further antimicrobial compound (ii) is selected from the following compounds:
-Β-lactams:
Penems, including carba-, thio- and oxapenems, such as imipenem, meropenem, ertapenem, biapenem, faropenem;
-Cephalosporins, such as cefazolin, cefepime, cefotaxime, defexitin, ceftaroline, ceftazidole, ceftobiprole, ceftriaxone, cefuroxime and cephalexin;
Monobactams, such as aztreonam, BAL 30072;
Penicillins such as penicillin G (benzylpenicillin), penicillin V, (phenoxymethylpenicillin); acylaminopenicillins such as piperacillin, mezlocillin, azurocilin; aminopenicillins such as ampicillin, amoxicillin; isoxazolyl penicillins such as oxacillin , Cloxacillin, dicloxacillin, flucloxacillin; methicillin; sultamicillin; ticarcillin, carbenicillin, temocillin;
β-lactams and β-lactamase inhibitors such as clavulanic acid + amoxicillin, sulbactam + ampicillin, tazobactam + piperacillin, ticarcillin + clavulanate, ceftazidime + abibactam, ceftaroline + abibactam, imipenem + MX-7655, biapenem + RPX 7009, azitreonam + Avibactam;
Fosfomycin;
Fosmidomycin;
Glycopeptides, such as teicoplanin, vancomycin;
Lipopeptides, such as daptomycin;
Lipoglycopeptides, such as telavancin, oritavancin, other agents active against dalbavancin gram-positive bacteria, such as GSK-1322222, AFN-1252, MUT-056399;
Polypeptides such as, for example, bacitracin, colistin, gramicidin, polymixin B, thyrotricin;
Other membrane-acting agents, such as brillicidin, POL 7080, ACHN-975;
Aminoglycosides, such as amikacin, gentamycin, kanamycin, neomycin, netilimycin, streptomycin, tobramycin;
Chloramphenicol, Tiamphenicol;
Fusidic acid;
Macrolides, such as azithromycin, clarithromycin, erythromycin, roxithromycin;
Ketolides, such as cetromycin, nalbomycin, tellithromycin, solitromycin;
Lincosamides, such as clindamycin, lincomycin;
Streptogramins such as dalfopristin, quinupristin;
Polyketides;
Oxazolidinones, such as linezolid, tedizolide, radezolide;
Tetracyclines, such as doxycycline, minocycline, tetracycline, oxycycline;
Glycyl cyclins such as tigecycline, omada cyclin;
Type II topoisomerase inhibitors:
Quinolones (in particular fluoroquinolones) such as norfloxacin, enoxacin, ciprofloxacin, ofloxacin, levofloxacin, gatifloxacin, gelepofloxacin, moxifloxacin, delafloxacin, finafloxacin, nemonoxacin, zabofloxacin, oxenoxacin Tinfloxacin, JNJ-Q2, DS-8587, KPI-10, GSK2140944, ACH-702;
Coumarins, novobiocin, chlorobiocin, coumermycin A;
Nitroimidazoles, such as metronidazole, tinidazole, ornidazole, nimorazole;
Folate agonists:
Sulfonamides, such as sulfadiazine, sulfadoxine, sulfamethoxazole, sulfasalazine;
Diamino pyrimidines such as pyrimethamine, trimethoprim;
Ansamycins:
Rifamycins, such as rifampicin, rifabutin, rifapentin, rifamixin;
Additional type:
Pleuromutilins, for example BC-3781, BC-7013;
Leucyl-t-RNA synthesis inhibitor, eg AN3365.

More preferably, the at least one further antimicrobial compound (ii) is selected from the following compounds:
Colistin, fosfomycin, tobramycin, ciprofloxacin, tigecycline, imipenem, piperacillin-tazobactam, ceftazidime, ampicillin, ceftriaxone, vancomycin, daptomycin, moxifloxacin and linezolid.

Particularly preferably, the at least one further antibacterial compound (ii) is selected from the following compounds:
Colistin, fosfomycin, ampicillin, ceftriaxone, moxifloxacin and linezolid.

および
７−（４−｛４−［（５Ｓ）−５−（アセチルアミノ−メチル）−２−オキソ−オキサゾリジン−３−イル］−２−フルオロ−フェノキシメチル｝−４−ホスホノオキシ−ピペリジン−１−イル）−１−シクロプロピル−６−フルオロ−４−オキソ−１，４−ジヒドロ−キノリン−３−カルボン酸：

またはその塩、溶媒和物もしくは水和物（例えば、７−（４−｛４−［（５Ｓ）−５−（アセチルアミノ−メチル）−２−オキソ−オキサゾリジン−３−イル］−２−フルオロ−フェノキシメチル｝−４−ホスホノオキシ−ピペリジン−１−イル）−１−シクロプロピル−６−フルオロ−４−オキソ−１，４−ジヒドロ−キノリン−３−カルボン酸のナトリウム塩）；そして
ここで、さらなる抗菌性化合物（ｉｉ）は次の化合物から選択される：
コリスチン、ホスホマイシン、アムピシリン、セフトリアキソン、モキシフロキサシンおよびリネゾリド。 In a particularly preferred embodiment, the present invention
Provided are combinations and / or pharmaceutical compositions and / or kits of parts comprising i) an oxazolidinone-quinolone hybrid and ii) a further antimicrobial compound different from compound (i), wherein the oxazolidinone-quinolone hybrid is 7 -(4- {4-[(5S) -5- (acetylamino-methyl) -2-oxo-oxazolidin-3-yl] -2-fluoro-phenoxymethyl} -4-hydroxy-piperidin-1-yl) -1-Cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid:

And 7- (4- {4-[(5S) -5- (acetylamino-methyl) -2-oxo-oxazolidin-3-yl] -2-fluoro-phenoxymethyl} -4-phosphonoxy-piperidine-1-) Yl) -1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid:

Or a salt, solvate or hydrate thereof (eg, 7- (4- {4-[(5S) -5- (acetylamino-methyl) -2-oxo-oxazolidin-3-yl] -2-fluoro) Sodium salt of phenoxymethyl} -4-phosphonooxy-piperidin-1-yl) -1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid); and Further antimicrobial compounds (ii) are selected from the following compounds:
Colistin, fosfomycin, ampicillin, ceftriaxone, moxifloxacin and linezolid.

  In a further preferred embodiment, the at least one further antimicrobial compound (ii) is selected from the following compounds: colistin and other polycations (or polycationic antimicrobials) such as bacitracin, gramicidin, polymyxin B, thyrothricin And aminoglycosides (eg, amikacin, gentamycin, kanamycin, neomycin, netilimicin, streptomycin and tobramycin).

  Particularly preferably, the further antibacterial compound (ii) is colistin.

  Colistin or other polycations (or polycationic antimicrobials) such as bacitracin, gramicidin, polymyxin B, thyrotricine, and aminoglycosides (eg amikacin, gentamycin, kanamycin, neomycin, netilimicin, streptomycin and tobramycin) additional antimicrobials If used as compound (ii), the corresponding pharmaceutical compositions and / or combinations according to the invention may be applied locally, for example to the eyes, ears, airways, skin and soft tissues, urethra and bladder, oral cavity, abdominal cavity or chest cavity It is preferred that it be generally applied to the surgical site. By gram-negative bacteria such as enterobacteria and non-fermentants including but not limited to isolates that produce ESBL and / or AmpC and multidrug and / or methicillin resistant staphylococci, such as but not limited to MRSA or MRSE) for the treatment or prevention of bacterial infections caused by gram-positive bacteria including multidrug and / or penicillin resistant Streptococcus (eg PRSP) and multidrug resistant and / or vancomycin resistant enterococci (eg VRE) In particular it can be used.

  Colistin or other polycations (or polycationic antimicrobials) such as bacitracin, gramicidin, polymyxin B, thyrotricine, and aminoglycosides (eg amikacin, gentamycin, kanamycin, neomycin, netilimicin, streptomycin and tobramycin) additional antimicrobials If used as compound (ii), it is further preferred that the corresponding pharmaceutical compositions and / or combinations of the present invention are applied parenterally. By gram-negative bacteria such as enterobacteria and non-fermentants including but not limited to isolates that produce ESBL and / or AmpC and multidrug and / or methicillin resistant staphylococci, such as but not limited to MRSA or MRSE) for the treatment or prevention of bacterial infections caused by gram-positive bacteria including multidrug and / or penicillin resistant Streptococcus (eg PRSP) and multidrug resistant and / or vancomycin resistant enterococci (eg VRE) In particular it can be used. Such infections include skin and soft tissue infections including cardiovascular, central nervous system, circulatory system, gastrointestinal tract, myco-genital organ, intra-abdominal, lower / upper respiratory tract, skeleton (bones and joints), and diabetic foot Disease is included.

In a further preferred embodiment, the at least one further antimicrobial compound (ii) is selected from the following compounds:
Fluoroquinolines, such as norfloxacin, enoxacin, ciprofloxacin, ofloxacin, levofloxacin, gatifloxacin, grepofloxacin, grepofloxacin, delofloxacin, delofloxacin, nemonoxacin, zabofloxacin, ozenoxacin, tinfloxacin, JNJ-Q ", DS-8587 , KPI-10, GSK 2140944, ACH-702 and finafloxacin, and oxazolidinones, such as linezolid, tedizolide and ladezolide.

  More particularly preferably, at least one further antimicrobial compound (ii) is selected from the following compounds: linezolid and moxifloxacin.

  Fluoroquinolines, such as norfloxacin, enoxacin, ciprofloxacin, ofloxacin, levofloxacin, gatifloxacin, grepofloxacin, grepofloxacin, delofloxacin, delofloxacin, nemonoxacin, zabofloxacin, ozenoxacin, tinfloxacin, JNJ-Q ", DS-8587 , KPI-10, GSK 2140944, ACH-702 and finafloxacin, and oxazolidinones such as linezolid, tedizolide and ladezolide (especially linezolid and moxifloxacin) as further antimicrobial compounds (ii). Corresponding pharmaceutical compositions and / or combinations according to the invention are bacterial infections, in particular β-lactams, quinolones (including fluoroquinolones), oxazolidines Preferably, it is used for the treatment or prevention of infections caused by multidrug-resistant bacteria, such as cardiovascular, central nervous system, circulatory system, gastrointestinal tract, secretorogenital organs, abdomen Included are skin and soft tissue infections, including the inner, lower / upper respiratory tract, skeletal (bone and joints), and diabetic feet.

In a further preferred embodiment, the at least one further antimicrobial compound (ii) is selected from the following compounds:
β-lactams such as amoxicillin, ampicillin, penicillin G (benzylpenicillin), penicillin V (phenoxymethylpenicillin), piperacillin, mezlocillin, azurocilin, oxacillin, cloxacillin, dicloxacillin, flucloxacillin, sultamicillin, carbenicillin, temocillin, ticarcillin, Imipenem, meropenem, ertapenem, faropenem, biapenem, cefazolin, cefepime, cefotaxime, cefoxitine, cefoxitin, ceftarodime, ceftabiprole, ceftriaxone, cephrexime, cephrexime, azithreonam and BAL 30072 and β-lactamases with β-lactamases Combinations, eg clavulanic acid + amoxicillin, sulbactam + a Pishirin, tazobactam + piperacillin, ticarcillin + clavulanate, ceftazidime + Abibakutamu, ceftaroline + Abibakutamu, imipenem + MX-7655, biapenem + RPX7009, Ajitoreonamu + Abibakutamu.

  More particularly preferably, the at least one further antibacterial compound (ii) is selected from the following compounds: ampicillin and ceftriaxone.

β-lactams such as amoxicillin, ampicillin, penicillin G (benzylpenicillin), penicillin V (phenoxymethylpenicillin), piperacillin, mezlocillin, azurocilin, oxacillin, cloxacillin, dicloxacillin, flucloxacillin, sultamicillin, carbenicillin, temocillin, ticarcillin, Imipenem, meropenem, ertapenem, faropenem, biapenem, cefazolin, cefepime, cefotaxime, cefoxitine, cefoxiline, ceftarodime, ceftaviprol, ceftriaxone, cephrexime, cephrexine, azithreonam and BAL 30072 or β-lactams and β-lactamase inhibitors Combinations, eg clavulanic acid + amoxicillin, sulbactam + a Picilin, tazobactam plus piperacillin, ticarcillin plus clavulanate, ceftazidime plus avibactam, ceftaroline plus abibactam, imipenem plus MX-7655, biapenem plus RPX 7009, azitreonam plus avibactam (especially ampicillin and ceftriaxone) are used as further antimicrobial compounds (ii) Therefore, the corresponding pharmaceutical compositions and / or combinations of the present invention are bacterial infections, in particular
Β-Lactam and / or multidrug resistance including but not limited to methicillin resistant staphylococci (eg MRSA, MRSE) and / or penicillin resistant Streptococcus (eg PRSP) and multidrug resistant and / or vancomycin resistant enterococci It is particularly preferred for use in the treatment or prevention of bacterial infections caused by gram positive bacteria. Such infections include skin and soft tissue infections including cardiovascular, central nervous system, circulatory system, gastrointestinal tract, myco-genital organ, intra-abdominal, lower / upper respiratory tract, skeleton (bones and joints), and diabetic foot Disease is included.

  In a further preferred embodiment, at least one further antibacterial compound (ii) is selected from the following compounds: vancomycin, daptomycin, tobramycin, ciprofloxacin, tigecycline, imipenem, piperacillin-tazobactam, telavancin, dalbavancin, oritavancin And ceftazidim.

  If the vancomycin, daptomycin, tobramycin, ciprofloxacin, tigecycline, imipenem, piperacillin-tazobactam, telavancin, dalbavancin, oritavancin or ceftazidime is used as the further antibacterial compound (ii), the corresponding pharmaceutical composition of the present invention and Preferably, the combination is used for the treatment and / or prevention of bacterial infections. In particular, such infections include the skin, including cardiovascular, central nervous system, circulatory system, gastrointestinal tract, urogenital, intraabdominal, lower / upper respiratory tract, skeleton (bones and joints), and diabetic feet Includes soft tissue infections.

  In a further preferred embodiment the at least one further antibacterial compound (ii) is selected from the following compounds: Fosfomycin, and other cell wall synthesis inhibitors such as, for example, β-lactams such as amoxicillin, penicillin G (benzyl penicillin ), Penicillin V (phenoxymethyl penicillin), piperacillin, mezlocillin, azlocillin, oxacillin, oxacillin, cloxacillin, dicloxacillin, flucloxacillin, sultamicillin, carbenicillin, temocillin, ticarcillin, imipenem, eropenem, eltapenem, faropenem, biapenem, cephalosporine, cephalosporine, , Cefoxitin, ceftaroline, ceftazidime, ceftobiprole, ceftriaxone, cefuroxime and cephalexin, azitreona And BAL 30072 and combinations of β-lactams and β-lactamases inhibitors, such as clavulanic acid + amoxicillin, sulbactam + ampicillin, tazobactam + piperacillin, ticarcillin + clavulanate, ceftazidim + avibactam, ceftaroline + avibactam, imipenem + MX-7655 , Biapenem + RPX 7009, Aditreonam + Avibactam.

  With further particular preference the further antimicrobial compound (ii) is fosfomycin.

  Fosfomycin, or other cell wall synthesis inhibitors such as beta-lactams such as amoxicillin, penicillin G (benzylpenicillin), penicillin V (phenoxymethylpenicillin), piperacillin, mezlocillin, azurocilin, oxacillin, cloxacillin, dicloxacillin, flucloxasi Phosphorus, sultamicillin, carbenicillin, temocillin, ticarcillin, imipenem, meropenem, ertapenem, faropenem, biapenem, cefazolin, cefepime, cefotaxime, cefoxirin, ceftaziprom, ceftobiprol, ceftriaxone, and A combination of a lactam and a β-lactamase inhibitor, for example clavula Acid + amoxicillin, sulbactam + ampicillin, tazobactam + piperacillin, ticarcillin + clavulanate, ceftazidim + avibactam, ceftaroline + abibactam, imipenem + MX-7655, biapenem + RPX 7009, azitreonam + avibactam (especially fosfomycin) as further antimicrobial compound (ii) If used, the corresponding pharmaceutical compositions and / or combinations of the invention are gram-negative bacteria such as enterobacteria and non-fermentants, including but not limited to isolates that produce ESBL and / or AmpC. And / or multidrug and / or methicillin resistant staphylococci (eg, MRSA or MRSE), multidrug and / or penicillin resistant Streptococcus (eg, PRSP) and multidrug Gender and / or vancomycin-resistant enterococci (eg, VRE) is preferably used particularly for the treatment or prevention of bacterial infections caused by Gram-positive bacteria, including.

In a further particularly preferred embodiment, the present invention provides a combination and / or pharmaceutical composition and / or kit of parts comprising i) an oxazolidinone-quinolone hybrid and ii) colistin, wherein the oxazolidinone-quinolone hybrid is Selected from Compounds:
7- (4- {4-[(5S) -5- (Acetylamino-methyl) -2-oxo-oxazolidin-3-yl] -2-fluoro-phenoxymethyl} -4-hydroxy-piperidin-1-yl ) -1-Cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid and 7- (4- {4-[(5S) -5- (acetylamino-methyl)-] 2-Oxo-oxazolidin-3-yl] -2-fluoro-phenoxymethyl} -4-phosphonoxy-piperidin-1-yl) -1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-quinoline -3-carboxylic acid or a salt thereof, such as 7- (4- {4-[(5S) -5- (acetylamino-methyl) -2-oxo-oxazolidin-3-yl] -2-fluo. - phenoxymethyl} -4-phosphonooxy - piperidin-1-yl) -1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro - quinoline-3-sodium salts of carboxylic acids.

In a further particularly preferred embodiment, the present invention provides a combination and / or pharmaceutical composition and / or a kit of parts comprising i) an oxazolidinone-quinolone hybrid and ii) linezolid, wherein the oxazolidinone-quinolone hybrid is Selected from Compounds:
7- (4- {4-[(5S) -5- (Acetylamino-methyl) -2-oxo-oxazolidin-3-yl] -2-fluoro-phenoxymethyl} -4-hydroxy-piperidin-1-yl ) -1-Cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid and 7- (4- {4-[(5S) -5- (acetylamino-methyl)-] 2-Oxo-oxazolidin-3-yl] -2-fluoro-phenoxymethyl} -4-phosphonoxy-piperidin-1-yl) -1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-quinoline -3-carboxylic acid or a salt thereof, such as 7- (4- {4-[(5S) -5- (acetylamino-methyl) -2-oxo-oxazolidin-3-yl] -2-fluo. - phenoxymethyl} -4-phosphonooxy - piperidin-1-yl) -1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro - quinoline-3-sodium salts of carboxylic acids.

In a further particularly preferred embodiment, the present invention provides a combination and / or a pharmaceutical composition and / or a kit of parts comprising i) an oxazolidinone-quinolone hybrid and ii) moxifloxacin, wherein an oxazolidinone-quinolone hybrid Is selected from the following compounds:
7- (4- {4-[(5S) -5- (Acetylamino-methyl) -2-oxo-oxazolidin-3-yl] -2-fluoro-phenoxymethyl} -4-hydroxy-piperidin-1-yl ) -1-Cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid and 7- (4- {4-[(5S) -5- (acetylamino-methyl)-] 2-Oxo-oxazolidin-3-yl] -2-fluoro-phenoxymethyl} -4-phosphonoxy-piperidin-1-yl) -1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-quinoline -3-carboxylic acid or a salt thereof, such as 7- (4- {4-[(5S) -5- (acetylamino-methyl) -2-oxo-oxazolidin-3-yl] -2-fluo. - phenoxymethyl} -4-phosphonooxy - piperidin-1-yl) -1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro - quinoline-3-sodium salts of carboxylic acids.

In a further particularly preferred embodiment, the present invention provides a combination and / or pharmaceutical composition and / or a kit of parts comprising i) an oxazolidinone-quinolone hybrid and ii) ampicillin, wherein the oxazolidinone-quinolone hybrid is Selected from Compounds:
7- (4- {4-[(5S) -5- (Acetylamino-methyl) -2-oxo-oxazolidin-3-yl] -2-fluoro-phenoxymethyl} -4-hydroxy-piperidin-1-yl ) -1-Cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid and 7- (4- {4-[(5S) -5- (acetylamino-methyl)-] 2-Oxo-oxazolidin-3-yl] -2-fluoro-phenoxymethyl} -4-phosphonoxy-piperidin-1-yl) -1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-quinoline -3-carboxylic acid or a salt thereof, such as 7- (4- {4-[(5S) -5- (acetylamino-methyl) -2-oxo-oxazolidin-3-yl] -2-fluo. - phenoxymethyl} -4-phosphonooxy - piperidin-1-yl) -1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro - quinoline-3-sodium salts of carboxylic acids.

In a further particularly preferred embodiment, the present invention provides a combination and / or a pharmaceutical composition and / or a kit of parts comprising i) an oxazolidinone-quinolone hybrid and ii) ceftriaxone, wherein the oxazolidinone-quinolone hybrid is Selected from the following compounds:
7- (4- {4-[(5S) -5- (Acetylamino-methyl) -2-oxo-oxazolidin-3-yl] -2-fluoro-phenoxymethyl} -4-hydroxy-piperidin-1-yl ) -1-Cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid and 7- (4- {4-[(5S) -5- (acetylamino-methyl)-] 2-Oxo-oxazolidin-3-yl] -2-fluoro-phenoxymethyl} -4-phosphonoxy-piperidin-1-yl) -1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-quinoline -3-carboxylic acid or a salt thereof, such as 7- (4- {4-[(5S) -5- (acetylamino-methyl) -2-oxo-oxazolidin-3-yl] -2-fluo. - phenoxymethyl} -4-phosphonooxy - piperidin-1-yl) -1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro - quinoline-3-sodium salts of carboxylic acids.

In a further particularly preferred embodiment, the present invention provides a combination and / or pharmaceutical composition and / or a kit of parts comprising i) an oxazolidinone-quinolone hybrid and ii) fosfomycin, wherein the oxazolidinone-quinolone hybrid is Selected from Compounds:
7- (4- {4-[(5S) -5- (Acetylamino-methyl) -2-oxo-oxazolidin-3-yl] -2-fluoro-phenoxymethyl} -4-hydroxy-piperidin-1-yl ) -1-Cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid and 7- (4- {4-[(5S) -5- (acetylamino-methyl)-] 2-Oxo-oxazolidin-3-yl] -2-fluoro-phenoxymethyl} -4-phosphonoxy-piperidin-1-yl) -1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-quinoline -3-carboxylic acid or a salt thereof, such as 7- (4- {4-[(5S) -5- (acetylamino-methyl) -2-oxo-oxazolidin-3-yl] -2-fluo. - phenoxymethyl} -4-phosphonooxy - piperidin-1-yl) -1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro - quinoline-3-sodium salts of carboxylic acids.

In a further particularly preferred embodiment, the invention provides i) 7- (4- {4-[(5S) -5- (acetylamino-methyl) -2-oxo-oxazolidin-3-yl] -2-fluoro-phenoxymethyl } -4-Hydroxy-piperidin-1-yl) -1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid ii) Combinations and / or pharmaceutical compositions comprising colistin And / or provide a kit of parts.

In a further particularly preferred embodiment, the present invention provides i) } -4-Hydroxy-piperidin-1-yl) -1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid ii) Combinations and / or pharmaceutical compositions comprising linezolid And / or provide a kit of parts.

In a further particularly preferred embodiment, the invention provides i) 7- (4- {4-[(5S) -5- (acetylamino-methyl) -2-oxo-oxazolidin-3-yl] -2-fluoro-phenoxymethyl } -4-Hydroxy-piperidin-1-yl) -1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid ii) Combinations and / or including moxifloxacin Pharmaceutical compositions and / or kits of parts are provided.

In a further particularly preferred embodiment, the invention provides i) 7- (4- {4-[(5S) -5- (acetylamino-methyl) -2-oxo-oxazolidin-3-yl] -2-fluoro-phenoxymethyl } 4-Hydroxy-piperidin-1-yl) -1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid ii) Combinations and / or pharmaceutical compositions comprising ampicillin And / or provide a kit of parts.

In a further particularly preferred embodiment, the invention provides i) 7- (4- {4-[(5S) -5- (acetylamino-methyl) -2-oxo-oxazolidin-3-yl] -2-fluoro-phenoxymethyl } -4-Hydroxy-piperidin-1-yl) -1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid ii) Combinations and / or medicaments comprising ceftriaxone Providing a composition and / or a kit of parts.

In a further particularly preferred embodiment, the invention provides i) 7- (4- {4-[(5S) -5- (acetylamino-methyl) -2-oxo-oxazolidin-3-yl] -2-fluoro-phenoxymethyl } -4-Hydroxy-piperidin-1-yl) -1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid ii) Combinations and / or pharmaceutical compositions comprising fosfomycin And / or provide a kit of parts.

In a further particularly preferred embodiment, the invention provides i) 7- (4- {4-[(5S) -5- (acetylamino-methyl) -2-oxo-oxazolidin-3-yl] -2-fluoro-phenoxymethyl } -4-Phosphonooxypiperidin-1-yl) -1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid sodium salt ii) Combinations comprising colistin and / or Or provide a pharmaceutical composition and / or a kit of parts.

In a further particularly preferred embodiment, the invention provides i) 7- (4- {4-[(5S) -5- (acetylamino-methyl) -2-oxo-oxazolidin-3-yl] -2-fluoro-phenoxymethyl } -4-Phosphonooxypiperidin-1-yl) -1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid sodium salt ii) Combinations comprising linezolid and / Or provide a pharmaceutical composition and / or a kit of parts.

In a further particularly preferred embodiment, the invention provides i) 7- (4- {4-[(5S) -5- (acetylamino-methyl) -2-oxo-oxazolidin-3-yl] -2-fluoro-phenoxymethyl Sodium salt of -4-phosphonooxypiperidin-1-yl) -1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid ii) including moxifloxacin Provided is a combination and / or pharmaceutical composition and / or kit of parts.

In a further particularly preferred embodiment, the invention provides i) 7- (4- {4-[(5S) -5- (acetylamino-methyl) -2-oxo-oxazolidin-3-yl] -2-fluoro-phenoxymethyl Sodium salts of) -4-Cyclophonooxypiperidin-1-yl) -1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid ii) Combinations comprising ampicillin and / or Or provide a pharmaceutical composition and / or a kit of parts.

In a further particularly preferred embodiment, the invention provides i) 7- (4- {4-[(5S) -5- (acetylamino-methyl) -2-oxo-oxazolidin-3-yl] -2-fluoro-phenoxymethyl } -4-Phosphonooxypiperidin-1-yl) -1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid sodium salt ii) Combinations comprising ceftriaxone And / or provide a pharmaceutical composition and / or a kit of parts.

In a further particularly preferred embodiment, the invention provides i) 7- (4- {4-[(5S) -5- (acetylamino-methyl) -2-oxo-oxazolidin-3-yl] -2-fluoro-phenoxymethyl Sodium salts of) 4-Cyclophonooxypiperidin-1-yl) -1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid ii) Combinations comprising fosfomycin and / Or provide a pharmaceutical composition and / or a kit of parts.

  The present invention also encompasses pharmacologically acceptable salts, or solvates and hydrates, respectively of Compounds (i) and (ii).

  Examples of pharmacologically acceptable salts of the sufficiently basic compounds (i) or (ii) are salts of physiologically acceptable mineral acids such as hydrochloric acid, hydroiodic acid, sulfuric acid and phosphoric acid; Or salts of organic acids such as methanesulfonic acid, p-toluenesulfonic acid, lactic acid, acetic acid, trifluoroacetic acid, citric acid, succinic acid, fumaric acid, maleic acid and salicylic acid. Furthermore, sufficiently acidic compounds (i) or (ii) are alkali or alkaline earth metal salts such as sodium, potassium, lithium, calcium or magnesium salts; ammonium salts; or organic base salts such as methylamine, dimethylamine, Trimethylamine, triethylamine, ethylenediamine, ethanolamine, choline, hydroxide, meglumine, piperidine, morpholine, tris- (2-hydroxyethyl) amine, lysine or arginine salts may be formed. The compounds (i) or (ii) may be solvated, in particular hydrated. Hydration occurs in the manufacturing process or as a result of the hygroscopic nature of the initially water-free compound (i) or (ii).

  The combinations according to the invention comprise at least two active compounds, which can be administered simultaneously, separately or at intervals. They can be provided, for example, in the form of a kit (e.g. kit of parts), and it is possible to separate and administer the oxazolidinone-quinolone hybrid (compound i) and the further antimicrobial agent (compound ii) Make it

  The weight ratio of oxazolidinone-quinolone hybrid (compound i) to the further antimicrobial compound (compound ii) may be in the range of 999: 1 to 1: 999.

  The weight ratio of oxazolidinone-quinolone hybrid (compound i) to the further antimicrobial compound (compound ii) is preferably in the range of 99: 1 to 1:99.

  Pharmaceutical compositions of the present invention comprise an oxazolidinone-quinolone hybrid (e.g., a compound of formula (I) or (II)) and a further antimicrobial compound. The pharmaceutical composition optionally further comprises a carrier and / or diluent and / or adjuvant. Optionally, the pharmaceutical composition of the invention may contain further additional antimicrobial compounds.

  The combinations (eg, pharmaceutical compositions) of the invention may be administered alone or in combination with other therapeutic agents using methods known and accepted in the art. They can be administered, for example, by one of the following routes: eg tablets, dragees, coated tablets, pills, semi-solid, soft or hard capsules, eg soft or hard gelatine capsules, aqueous or oily solutions, emulsions, suspensions Oral administration as a liquid or syrup, eg parenteral administration, including intravenous, intramuscular and subcutaneous injection as infusion solution or suspension, rectal administration as a suppository, eg powder formulations, microcrystalline or spray (eg , Administration by inhalation or as a liquid aerosol), transdermal administration by means of a transdermal delivery system (TDS) such as an active ingredient-containing plaster, or, for example, ointments, pastes, drops, lotions, as solutions eg skin, mucous membranes , Eyes or ears, or nose in the mouth, abdominal cavity or pleural cavity Inner or topical administration. For the manufacture of such tablets, pills, semisolids, coated tablets, dragees, and hard (eg gelatin) capsules, the therapeutically useful product is a pharmaceutically inert inorganic or organic excipient such as It may be mixed with lactose, sucrose, glucose, gelatin, malt, silica gel, starch or its conductor, talc, stearic acid or its salt, dried skimmed milk and the like. In the case of soft capsule manufacture, excipients such as, for example, plant, petroleum, animal or synthetic oils, waxes, fats, polyols etc. may be used. In the case of liquid solutions (eg, drops), emulsions or suspensions or syrups, water, alcohol, saline, aqueous dextrose, polyols, glycerin, lipids, phospholipids, cyclodextrins, plants, petroleum, animals or synthetic oils It can be used. Particularly preferred are lipids, more preferably phospholipids (preferably natural; preferably in phosphate buffered saline (pH = 7-8, preferably 7.4), particularly preferably with a particle size of 300. ~ 350 nm). In the case of suppositories, excipients such as plants, petroleum, animal or synthetic oils, waxes, fats and polyols may be used. In the case of aerosol formulations, compressed gases suitable for this purpose such as oxygen, nitrogen and carbon dioxide may be used. Pharmaceutically useful agents also contain additives for storage and stability, such as UV stabilizers, emulsifiers, sweeteners, fragrances, fragrances, salts for altering the osmotic pressure, buffers, coating additives and antioxidants It can.

  The daily dose per patient of the combination (for example, the composition) of the present invention is usually about 1 mg to about 10 g, especially about 50 mg to about 3 g. It is understood that it depends on the condition of the patient being treated and the type of disease being treated or prevented. The daily dose can be administered at once or divided into several doses. The average dose at one time may be about 50 mg, 100 mg, 250 mg, 500 mg, 1000 mg and 2000 mg. The combination of the invention can also be used as a sterilizing agent for surgical instruments.

1. Materials and Methods 1.1 MIC determination and time-kill analysis The minimum inhibitory concentration (MIC) (see Section 1.3) of Compound 1 against test and quality control strains is determined by cation-adjusted Mueller-Hinton agar (CAMHB). Measurements were made twice in duplicate by the agar microdilution method according to the CLSI guidelines (Clinical and Laboratory Standards Institute (CLSI)) in Japan; the M07-A8 method for diluted antimicrobial susceptibility testing against aerobically growing bacteria: acceptance criteria 8th edition 2009; Clinical and Laboratory Standards Institute, Wayne, PA. Two-fold serial dilutions (256-0.03 mg / L) in CAMHB using 10 mL plastic tubes were aliquoted into empty round bottom 96 well plates.

  MIC testing was performed immediately after preparation of the dilution. All tests were repeated in duplicate and one more time. The data reported in the results section (see section 2) showed higher MIC values for outliers, which were rarely recorded.

  Test strains that were not exposed served as growth controls. Moxifloxacin was used as a quality control drug. S. aureus ATCC 29212, E.I. Fecalis ATCC 29212, Streptococcus pneumoniae ATCC 49619 and 33400, E. coli ATCC 25922 and Pseudomonas aeruginosa ATCC 10145 were quality control strains recommended by the CLSI guidelines. In general, all quality controls were acceptable in either test, not only to the control drug moxifloxacin, but also to all other tested antimicrobials (see section 1.2) ).

  Killing curve kinetics were measured in duplicate according to the CLSI guidelines (Clinical and Laboratory Standards Institute (CLSI)); M07-A8 method for diluted antimicrobial susceptibility testing against aerobically growing bacteria: acceptance criteria; 8th edition 2009 Clinical and Laboratory Standards Institute, Wayne, PA). Sampling for quantification of viable counts ceased at 0, 1, 2, 4, 6, 8, and 24 hours.

The single point kill rate (k) is given by (N ₀ and N _t = 0 and the number of viable bacteria at time t):
k ^(h-1) = (ln (N _t / N ₀ ) / t
(Schaper K. J., Schubert S., Dalhoff A., Kinetics of the antibacterial effect of .BETA.-lactams, macrolides and quinolones against Gram-positive and Gram-negative RTI-pathogens as calculated above using And quantification: Infection 2005; 33 (supplement 2): 3-14).

この化合物はＷ２００５／０５８８８８に記載の手順に従って製造した。次の試験では、化合物１はＤＭＳＯに溶解、希釈した。 1.2 Oxazolidinone-Quinolone Hybrid (Compound 1) and Combination Drug Compound 1:
7- (4- {4-[(5S) -5- (Acetylamino-methyl) -2-oxo-oxazolidin-3-yl] -2-fluoro-phenoxymethyl} -4-hydroxy-piperidin-1-yl ) -1-Cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid:

This compound was prepared according to the procedure described in W2005 / 058888. In the next test, Compound 1 was dissolved and diluted in DMSO.

The following antibacterial agents have been selected as combination drugs based on antibacterial range and therapeutic applications where treatment of bacterial infections due to gram positive and gram negative pathogens is difficult (ie antibacterial compound ii; hereinafter "combination drug") :
Colistin CF 80 mg powder = 33.3 mg pure colistin, Gruenenthal GmbH, & Co KG, Aachen, 52078 (batch No. 111 C06) fosfomycin, phosphosina, 4 g injection solution, Laboratorios ERN, S. et al. A. , Spain, Barcelona, E-8020 (batch No. E014)
Ciprofloxacia Kabi, 400 mg / 200 mL infusion solution, Fresenius Kabi Deutschland GmbH, Hamburg, Germany, Bad BAD, D-61352 (Batch No. 15FC145F2)
Moxifloxacin, Bayer Vital GmbH, Germany, Leverkusen, D-51368 (batch No. BXGON 82)
Ampicillin, 1.06 g powder = 1.0 g pure substance, Germany, Ratiopharm, Germany, Ulm, D-89079 (batch No. L46849)
Ceftazidime, Fortam 2.0 g, 2.606 g powder = 2.328 g pure substance, MIP Pharma, Briescaster, D-66440 (batch No. 1012)
Ceftriaxone, Ceftriaxone-Saar, 1.193 g Powder = 1.0 g Pure substance, MIP Pharma, Briescaster, D-66440 (Batch No. 2355000)
Imipenem, Dienum 500 mg / 500 mg (Imipenem + Silastatin), MSD Sharp & Dohme GmbH, Haar, Germany, D-85540 (Batch No. 2050470)
Piperacillin / tazobactam, Tazobac EF 4 g / 0.5 g, Pfizer Pharma GmbH, Berlin, D-10785 (batch No. AH2R / 21)
Daptomycin, cubicin 500 mg, infusion solution, Novartis Europharm Ltd. , UK, Horsham, RH 12 5 AB (Batch No. CDC153D)
Linezolid, divoxide 2 mg / mL infusion solution, Pfizer Pharma GmbH, Berlin, D-10785 (Batch No. 12B08U10)
Tobramycin, Gerebrus 80 mg / 2 mL Infusion Solution, Infectopharm Arzneimittel und Consilium GmbH, Heppenheim, D-64630 (Batch No. W081102.1)
Vancomycin, vancomycin CP 500 mg, 512 mg powder = 500 mg pure substance, Hikma Pharma GmbH, Griffell, D-82166 (batch No. 111204.1)
Tigecycline, Tigesil 50 mg infusion solution, Wyeth Europe Ltd., Berkshire, UK, SL60PH (batch No. F75592)

1.3 Tests and Quality Control Strains Test strains were selected based on specific and difficult antimicrobial susceptibility patterns that make handling of the resistance mechanism; they are the current clinical causes of respiratory tract or skin and soft tissue infections or other infectious diseases Does not represent strains that are considered to be of

Generally, one sensitive wild-type strain per species was included in the panel of test strains. This susceptible strain was often identical to the ATCC quality control strain described in Section 1.1; additional ATCC sensitive wild-type strains are shown below:

Gram-negative bacteria E. coli ATCC 25922 (quality control for MIC testing)
E. coli NRZ-00401 (metallo β-lactamase VIM-1)
E. coli NRZ-00302 (metallo β-lactamase NDM-1)
E. coli GNS-2601 (ESBL CTX-M-15)
P. pneumoniae ATCC 13883 (quality control for MIC testing)
Klebsiella pneumoniae NRZ-00002 (OXA-48)
Klebsiella pneumoniae NRZ-00535 (VIM-1)
Klebsiella pneumoniae NRZ-00103 (KPC-2)
P. Mirabilis ATCC 9240 (sensitive wild type)
P. Mirabilith NRZ-00185 (AmpC, type CMY-2)
Pseudomonas aeruginosa ATCC 10145 (quality control for MIC testing)
Pseudomonas aeruginosa NRZ-00425 (VIM-1)
E. Black locust ATCC 13047 (sensitive wild type)
E. Black stingray NRZ-00239 (VIM-1)

Gram-positive bacteria Staphylococcus aureus ATCC 29213 (quality control for killing curve analysis)
Staphylococcus aureus RNG1GH 001 (Quality Control for Killing Curve Analysis)
Staphylococcus aureus DSM 11823 (MSSA, quinolone resistance)
Staphylococcus aureus ATCC 33593 (MRSA)
Staphylococcus aureus NRS-119 (MRSA, linezolid- and quinolone-resistant)
Staphylococcus aureus Visa Mu 50 (MRSA, vancomycin moderately sensitive E. faecalis ATCC 29212 (quality control)
E. Fecaris V583 (Van B)
E. Fesium DSMZ 2146 (sensitive wild type)
E. Fesium UW 3695 (linezolid and quinolone resistant)
Streptococcus pneumoniae ATCC 49619 (quality control for MIC test)
Streptococcus pneumoniae ATCC 33400 (sensitive wild type)
Streptococcus pneumoniae BAY 19397 (penicillin-, macrolide-, quinolone-resistance)

1.4 Media Cation-adjusted Mueller-Hinton agar (CAMHB) (Dickinson-Diagnostics, Heidelberg, Germany, D-69126) was used.

1.5 Preparation of Inoculum The test strain was subcultured on Columbia agar and cultured overnight at 36 ° C ± 1 ° C.
Inoculate tubes containing 3-5 mL sterile 0.85% NaCl into 5 or more colonies from agar plates, The turbidity was adjusted to 1 × 10 8 CFU / mL corresponding to 0.5 McFarland standard.
One mL of bacterial suspension was transferred to a tube containing 10 mL CAMHB and vortexed well. (1 mL of Streptococcus pneumoniae in 10 mL CAMHB + 5% lysed equine blood). 5 μl of this suspension was inoculated in columns 1-15 of a 96-well plate (1-15 = antibacterial solution, 16 = sterile medium without test material).
Plates were shaken carefully for about 5 minutes and incubated at 36 ° C. for 18-24 hours.
The turbidity was read visually with a mirror.
Final volume: 105 μL (100 μL of antibacterial solution, 5 μL of bacterial suspension)
Final bacterial concentration: 5 x 10 5 CFU / mL
Final antimicrobial concentration: 0.06 to 16 mg / L

1.6 Synergism test and FIC index The synergy test was carried out in three ways (Neu HC, Fu KP P. azlocillin and mezlocillin combined with aminoglycoside antibiotics and cephalosporin. Antimicrob Agents Chemother 1978; 13 (5): 813-819):
1. Two combination drugs were added at increasing concentrations starting from a concentration corresponding to 1/2 (0.5) of the lowest inhibitory concentration (MIC) of Compound 1.
2. Using the death curve method, combinations of one combination drug and compound 1 were evaluated at a concentration corresponding to 1 + 1, 1 + 2, 2 + 1 and 2 + 2 times their MIC. The time-kill test was performed by adding the combined antimicrobials to log phase E. coli cultures (10 mL) diluted to 105-106 CFU / mL and grown in a 50 mL flask at 37 ° C.
3.1 Checkerboard 2-fold dilution method with one combination drug and Compound 1 per analysis (Pillai, S., Moellering R., Eliopoulos G. Antimicrobial combination, In V. Lorian (Editor), Antibiotics in Laboratory medicine, 5th edition, Lippincott Willams & wilkins, Baltimore, MD, 2005, pp. 365-440).

Checkerboard, Partial Inhibitory Concentration (FIC) and FIC Index:
The liquid medium microdilution sterilizing checkerboard method was used as described above (Pillai, S., Moellering R., Eliopoulos G. Antibacterial Combination, In V. Lorian (Editor), Antibiotics in laboratory medicine 5 edition, Lippincott Willams & wilkins, Maryland, Baltimore, 2005, pp. 365-440). Serial dilutions of two antimicrobial agents A and B (ie, one combination drug and compound 1) were tested. The checkerboard has a column in which each well contains the same amount of antimicrobial agent A on i dilution along the x axis, and a column in which each well contains the same amount of antimicrobial agent B on j dilution on the y axis It consists of each column. That is, serial dilutions of antimicrobial agents A and B are each titrated in a rectangular fashion. The result is that each well contains various combinations of the two antimicrobials, thereby combining each concentration of antimicrobial A with each concentration of antimicrobial B. Growth and sterility controls were included in all plates. Bacterial inoculum (prepared as described above) at 5 × 10 5 CFU / mL was used. The microtiter tray was incubated at 37 ° C. for 18 hours.

Partial inhibitory concentration (FIC) is a mathematical expression of the effect of the combination of the two antimicrobials A and B. FIC was calculated by dividing the MIC of the combination of antibacterial agent A and antibacterial agent B by the MIC of antibacterial agent A or antibacterial agent B alone. The FTC index is believed to characterize whether the combination has a synergistic, additive, neutral or antagonistic effect (the term relates to methods for measuring the susceptibility of bacteria to antimicrobials. Clinical microbiology and infections Antimicrobial Susceptibility Testing of the European Association for Sexual Illness (ESCMID) European Commission (EUCAST) EUCAST definitive document E. Def 1.2; Clin Microbiol Infect Dis 2000; 6: 503-508):
-Synergism was defined as FIC index less than 0.5.
-Additive or neutral effects were defined as FIC index 0.5 to 4 (additional effects> 0.5 to 1; neutral effects> 1 to 4).
-Antagonism was defined as FIC index 4 or higher.

The FIC index is calculated according to the following formula:

FIC _(A) = MIC ₍ Niorkel _{A in the} presence of _{B )} / MIC _(A only ₎

FIC _(B) = MIC ₍ Niorkel _{B in the} presence of _{A )} / MIC _(B alone ₎

FIC index = FIC _(A) + FIC _(B)

2. Results 2.1 Quality Control The internationally accepted strains E. coli ATCC 25922, K. pneumoniae ATCC 13833 and P. aeruginosa ATCC 10145 were used as quality control strains for susceptibility testing. The MICs of the various agents tested against these quality control strains were within the acceptable range as defined by CLSI.

  S. aureus ATCC 29213 and S. aureus RNGlGH 001 were used as quality controls for time-kill experiments, in addition to the ATCC reference strains used as quality controls for MIC testing. S. aureus ATCC 29213 was exposed to moxifloxacin at seven separate times during this study; moxifloxacin was selected as the reference drug. In addition, the strain S. aureus RNG1 GH001 sensitive to compound 1 could be exposed at different times to different concentrations of compound 1 so that the reproducibility of the antibacterial effect of compound 1 could be investigated.

2.2 MIC Testing of Compound 1 in the Presence of Combination Drugs Combination testing was performed at or below the inhibitory concentration corresponding to 0.5 of each MIC of the various combination drugs (see Section 1.6), and thus, individual combinations Because it is not the MIC of the drug, the values shown below in Tables 1A-1C and 2A-2C represent the MIC of the corresponding single substance, or (for the combination test) the MIC of Compound 1 alone.
The experiment reported in Table 1A was repeated three times; Tables 1B and 1C, and all other tests reported in Tables 2A, 2B and 2C were repeated once.

Activity against gram negative bacteria (see Tables 1A, B and C)
Colistin, fosfomycin: Compound 1 exhibits low activity against enterobacteria or non-fermentants. Colistin is active against intestinal bacteria but not against the P. aeruginosa strains tested. Fosfomycin was tested against E. coli which showed only heterogeneous activity.

The combination of Compound 1 and colistin reduced the MIC of Compound 1 against enterobacteria until the 6 or even 9 titration steps (Table 1A).
The combination of Compound 1 and fosfomycin reduced the MIC of Compound 1 to 2-3 titration steps against 2 E. coli and to> 9 titration steps against the remaining colon test strains (Table 1A).

Table 1A: Antibacterial activity (MIC at mg / L) of single substance compound 1, colistin and fosfomycin, or a combination of compound 1 and 0.5 times MIC with each of colistin and fosfomycin (Ec = E. coli; Kp = Klebsiella pneumoniae Pm = P. Mirabilis; Pa = P. Aeruginosa; Ecl = E. Cloacae; MCB = compound 1; fosfo = fosfomycin; nt = not tested)

  Tobramycin, ciprofloxacin, tigecycline: Tobramycin is a sensitive wild type strain only as well as CMY-2 producing P. It was active against mirabilis strains; tobramycin MIC exceeded 4 mg / L against the remaining test strains. Ciprofloxacin was active against the wild type strain and against two β-lactamase producing strains (E. coli NRZ-00401 and P. mirabilis NRZ-00103). The ciprofloxacin MIC exceeded 16 mg / L for the remaining test strains. The combination of Compound 1 and ciprofloxacin lowered the MIC of Compound 1 of all test strains. The MIC of compound 1 of the wild type strain was significantly reduced, but the MIC of compound 1 of the selected resistant strain was not affected (Table 1B). Tigecycline suppressed the reference strain E. coli ATCC 25922 at 0.5 mg / L; all other test strains were suppressed by tigecycline concentration> 2 mg / L. The combination of Compound 1 + Tigecycline did not affect the activity of Compound 1 against these gram negative test strains (Table 1B).

Table 1 B. Antimicrobial activity of single substance compound 1, tobramycin, ciprofloxacin, tigecycline, or a combination of compound 1 and 0.5 times MIC of tobramycin, ciprofloxacin and tigecycline respectively (mg / L MIC) (Ec = E. coli; Kp = K. pneumoniae; Pm = P. mirabilis; Pa = P. aeruginosa; Ecl = E. black stunt; MCB = compound 1; tob = tobramycin; cip = ciprofloxacin; tige = tigecycline )

  Among the beta-lactams tested: imipenem, piperacillin / tazobactam, ceftazidime: imipenem was the most active; it was all at a concentration of <8 mg / L except for P. aeruginosa NRZ-00185 and Klebsiella pneumoniae NRZ-00103 Test strains were inhibited (Table 1C). The combination of Compound 1 and imipenem did not affect the MIC of Compound 1. Piperacillin / tazobactam contains wild type E. coli, Klebsiella pneumoniae and P. pylori. The activity of the remaining strains was> 4 mg / L. The combination of compound 1 and piperacillin / tazobactam lowered the MICs of the three test strains by 2-3 dilution steps (E. coli ATCC 25922, E. coli GNS 2601; P. aeruginosa ATCC 10145), but affected the activity of compound 1 against other test strains. It was not. Ceftazidime is Escherichia coli, P. pneumoniae and The Milabiris wild type strain was suppressed at low concentrations <0.5 mg / L; the MIC of the remaining strains exceeded 2 mg / L. The combination of compound 1 and ceftazidime was significantly active against the two P. aeruginosa strains but did not affect the activity of compound 1 against the other test strains (Table 1C).

Table 1 C. Single substance compound 1, imipenem, piperacillin / tazobactam, ceftazidime, or the antibacterial activity (MIC at mg / L) of a combination of compound 1 and imipenem of 0.5 times MIC, piperacillin / tazobactam, ceftazidime respectively (Ec) = E. coli; Kp = K. pneumoniae; Pm = P. mirabilis; Pa = P. aeruginosa; Ecl = E. cloacae; MCB = compound 1; imi = imipenem; P / T = piperacillin / tazobactam; cef = ceftazidime; Data was reproducible twice but not constant at other time points; nt = not tested)

Activity against Gram-positive bacteria (see Tables 2A, B and C)
Compound 1 was active against all Gram-positive strains tested regardless of sensitivity pattern; wild-type strains were suppressed as well as multi-drug resistant strains by Compound 1 concentrations of <0.25 mg / L (Tables 2A to 2C).

  Ampicillin, Ceftriaxone: The beta-lactams Ampicillin and Ceftriaxone were active against only wild type or MSSA strains (Table 2A). The combination of Compound 1 and both β-lactams, in combination with ampicillin against most of the tested strains except MRSA strain NRS-119 and Visa Mu 50, allows for a range of tolerance (+/- 1-2 titration steps Within the same activity as Compound 1 alone, and for those strains, the MIC of Compound 1 dropped from 1 to 0.25 mg / L and from 0.06 to <0.00003 mg / L respectively; . The MIC of Compound 1 in the case of Fesium DSMZ 2146 also fell from 0.06 to <0.00003 mg / L. The MIC of Compound 1 in the case of Streptococcus pneumoniae 19397 dropped from 0.004 to <0.00003 mg / L when combined with Ceftriaxone (Table 2A).

Table 2A Antibacterial activity (MIC at mg / l) of single substance compound 1, ampicillin and futriaxone, or a combination of compound 1 and 0.5 times MIC of ampicillin and futriaxone (MCB = compound 1; ampi = ampicillin; ceftr = ceftriaxone; Sa = S. aureus; Ef = E. faecalis; Efc = E. fecium; Spn = Streptococcus pneumoniae; * = These data were reproducible twice but were constant at other time points Did not do)

  Vancomycin, daptomycin: vancomycin and daptomycin may be used as the vancomycin resistant strain E. coli. The activity was against all Gram-positive strains tested except for Fecaris V583, to which the vancomycin MIC was 32 mg / L and the daptomycin MIC was 4 mg / L. The combination of Compound 1 with either vancomycin or daptomycin was as active as single Compound 1 against these test strains within the range of variation (Table 2B).

Table 2B Antibacterial activity (MIC at mg / l) of single substance compound 1, vancomycin and daptomycin, or a combination of compound 1 and 0.5 times MIC vancomycin and daptomycin (MCB = compound 1; vanco = vancomycin dapto = daptomycin; Sa = Staphylococcus aureus; Ef = E. faecalis; Efc = E. fecium; Spn = Streptococcus pneumoniae; * = These data were reproducible twice but were not constant at other time points )

  Moxifloxacin, linezolid, tigecycline: Moxifloxacin is S. aureus NRS-119 and Visa Mu 50, linezolid- and quinolone resistant E. coli. It showed good activity against most Gram-positive strains tested except for Fesium UW 3695 and multidrug resistant Streptococcus pneumoniae 19397. Linezolid has been reported to be S. aureus NRS-119 and E. coli. All tested strains except for Fesium UW 3695 were inhibited at a concentration <4 mg / L. Tigecycline was active at all concentrations <0.5 mg / L against the tested strains (Table 2C). The combination of compound 1 and moxifloxacin was as active as the single substance against staphylococcal ATCC 29213, clone 16 and ATCC 33593; however, compound 1 gained activity against all other test strains, The MIC dropped to <0.000025 mg / L. Similarly, the combination of Compound 1 and Linezolid was similar to Compound 1 alone against Staphylococcal ATCC 29213, Clone 16 and ATCC 33593; however, Compound 1 was a combination of Linezolid against all other tested strains. Activity was obtained, and the MIC was reduced to <0.000001 mg / L. (For the quinolone- and linezolid-resistant strain E. faecalis UW 3695, the combined MIC was 2 mg / L compared to 0.06 mg / L for Compound 1 alone) (Table 2C).

Table 2C Antibacterial activity of single substance compound 1, moxifloxacin, linezolid and tigecycline, or a combination of compound 1 and 0.5 times MIC of moxifloxacin, linezolid and tigecycline (mg / l MIC) (MCB = Compound 1; mox = moxifloxacin; line = linezolid; tige = tigecycline; Sa = S. aureus; Ef = E. faecalis; Efc = E. fecium; These data were reproducible twice but were not constant at other times)

2.3 Time-kill curve of Compound 1 in the presence of colistin and fosfomycin The time-dependent effect on the viable count of the combination of Compound 1 with colistin and fosfomycin was determined. The viable counts recorded at 8 hours are summarized in Tables 3A and 3B. The calculated kill rates are shown in Tables 4A and 4B.

The strains E. coli ATCC 25922, NRZ-00401, NRZ-00302 and GNS-2601 were exposed to combinations of colistin and fosfomycin, respectively, with compound 1 with their 1- and 2-fold MIC. The following combinations of these agents were tested:
-1 x MIC compound 1 + 1 x MIC colistin or fosfomycin (1 + 1)
-1 x MIC compound 1 + 2 x MIC colistin or fosfomycin (1 + 2)
2 × MIC compound 1 + 1 × MIC colistin or fosfomycin (2 + 1)
-2 x MIC compound 1 + 2 x MIC colistin or fosfomycin (2 + 2)

  Compound 1 at 1 or 2 times MIC exhibits bacteriostatic activity against these Gram negative test strains for the first 4 to 6 hours; thereafter, the strains re-grow. Similarly, fosfomycin acts bacteriostatically against strain ATCC 25922, NRZ-00401, but is bactericidal against strains NRZ-00302 and GNS-2601, however, the latter two strains were absent from the test system Not (Table 3A). Colistin is bactericidal against the four E. coli strains tested, and the viable count was reduced to a viable count below the detection limit within 6 to 8 hours (except for the NRZ-00302 strain, which is within 8 hours). It decreased significantly and disappeared within 24 hours) (Table 3B).

The combination of Compound 1 and Fosfomycin in 1 + 1 and 2 + 1 ratio was bacteriostatic against strains ATCC 25922 and NRZ-00401, but prevented regrowth unlike exposure to Compound 1 alone. The 1 + 2 combination reduced the viable count of strain ATCC 25922 to 0.7 log ₁₀ CFU / mL in 8 hours, but a 3.9 log ₁₀ CFU / mL regrowth was observed thereafter (Table 3A). The 2 + 2 combination eliminated the test strain E. coli ATCC 25922 from the system within 24 hours. Strain NRZ-00401 was bacteriostatically affected by the combination of 1 + 1 and 2 + 1, but the 1 + 2 combination reduced the viable count to 2.9 log ₁₀ CFU / mL within 8 hours and then regrown. Strains NRZ-00302 and GNS-2601 disappeared within 24 hours due to any combination ratio of Compound 1 + Fosfomycin tested from the test system.

Table 3A Viable counts (log ₁₀ CFU) at 1 hour exposure of 1-fold (1 ×) or 2-fold (2 ×) MIC compound 1 (MCB), fosfomycin (fosfo), or a combination of the two agents

  Any combination of Compound 1 and colistin caused the strain to disappear from the test system as well as colistin alone within 24 hours (Table 3B).

Table 3B Viable counts (log ₁₀ CFU) at 1 hour exposure of 1x (1x) or 2x (2x) MIC of compound 1 (MCB), colistin (col), or a combination of two agents

The expansion of the decrease in viable count of E. coli tested, in particular the increase in the activity of the combination of Compound 1 + fosfomycin, also reflects that the rate of decrease in viable count is accelerated. The data summarized in Tables 4A and 4B represent the kill rates calculated for the first 4 hours of exposure to single substances or combinations thereof. The data summarized in Table 4A show that single substance 1 and fosfomycin alone reduce the growth rate of two of the four strains. The combination of the two agents reduced the viable count at a kill rate of 1.01-2.38 h ^-1 .

TABLE 4A Effects of 1x (1x) or 2x (2x) MICs on the kill rates of the four test E. coli strains, respectively, of Compound 1 (MCB), Fosfomycin (fosfo), or a combination of two agents. A positive value ("+") indicates growth and all remaining values are negative indicating the rate of decline of viable count, ie, the rate of kill k (h ^-1 ).

  The significant bactericidal activity of colistin against test E. coli strains was not increased by the combination of strain colistin and compound 1 (except E. coli ATCC 25922) (Table 4B).

Table 4B Effects of 1-fold (1 ×) or 2-fold (2 ×) MICs on the growth and kill rates, respectively, of test E. coli strains of Compound 1 (MCB), colistin (col), or a combination of the two agents. A positive value ("+") indicates growth and all remaining values are negative indicating the rate of decline of viable count, ie, the rate of kill k (h ^-1 ).

2.4 Checkerboard titration of Compound 1 and colistin Checkerboard titration was performed three times. Compound 1 at each concentration <0.015 to 256 mg / L was combined with colistin at each concentration <0.015 to 256 mg / L.

Test strains E. coli ATCC 25922 (sensitivity reference strain), E. coli NRZ-00302 (NDM-1 beta-lactamase), Klebsiella pneumoniae NRZ-00535 (VIM-1 beta-lactamase), Pseudomonas aeruginosa NRZ-00425 (VIM-2 beta-lactamase) ), E. Black stunt ATCC 13047 (sensitivity reference strain) and E. coli. The black stunt ANRZ-00239 (VIM-1 beta-lactamase) was exposed to each concentration of Compound 1 and colistin.
In general, the MIC of Compound 1 is reduced to less than 0.015 mg / L in combination with 2 or at least 4-fold colistin MICs, while the combination with colistin concentrations lower than 0.25-fold MICs is lower than E. coli. The MICs of Compound 1 had no effect on most of the test strains except for the black locust ATCC13047. E. The black locust ATCC 13047 is resistant to colistin with a MIC of 256 mg / L; the combination of Compound 1 and a colistin concentration of 128 mg / L results in a reduction of the MIC of Compound 1 from> 256 mg / L to 1-0.5 mg / L Even at a low colistin concentration of 2 mg / L, the MIC of Compound 1 was reduced to 1-4 mg / L.

  The data summarized in Table 5 are below the inhibitory concentration (ie 0.5 times MIC), the inhibitory concentration (ie 1.0 times MIC) and above the inhibitory concentrations (ie 2.0 times and 4.0 times 6 shows the combined effect of MIC) on colistin.

  The data summarized in Table 5 show that inhibitory concentrations and colistin concentrations above inhibitory concentrations reduce the MIC of Compound 1 from> 256 mg / L to <0.015 mg / L. In the case of combination with compound 1, FIC is 0.5 to 1.8 for colistin below the suppression concentration, 1.0 to 2.0 for colistin concentration for the suppression concentration, 2.0 to 2.0 for colistin concentration above the suppression concentration Indicates the range of 4.0.

＊ コリスチンＭＩＣは２５６ｍｇ／Ｌだったので、コリスチンの限界溶解度のため、化合物１と２および４倍コリスチンＭＩＣとの組み合わせは試験しなかった。 Checkerboard titration of the combination of Compound 1 and colistin against six selected indicator strains. The following strains were tested: E. coli ATCC 25922 (Ec ATCC); E. coli NRZ-00302 (Ec NRZ), K. pneumoniae NRZ-00535 (kpn NRZ), P. aeruginosa NRZ-00425 (Pa NRZ), E. coli. Black stunt ATCC 13047 (Ecl ATCC) and E. coli. Scutellariae ANRZ-00239 (Ecl NRZ). (Parameter: MIC in mg / L); MCB MIC = MIC of compound 1; col MIC = MIC of colistin; MCB + 0.5 col = 0.5 times MIC of compound 1 in the presence of colistin MIC; MCB + 1.0 col = MIC of Compound 1 in the presence of 1.0 fold colistin MIC; MIC of Compound 1 in the presence of MCB + 2.0 col = 2.0 fold colistin MIC; MCB + 4.0 col = 4.0 fold in the presence of colistin MIC MIC of compound 1 of the following; MIC of compound 1 in the presence of MCB + 5.0 col = 5.0 × colistin MIC; FIC in 0.5 col = FIC index in the presence of 0.5 × colistin MIC; FIC in 1.0 col = 1. FIC index in the presence of 0 × colistin MIC; FIC ind 2.0 col = 2.0 FIC index in the presence of colistin MIC; FICind4.0col = 4.0 times FIC index in the presence of colistin MIC; FIC index represents an average of the results of two or three tests or single test.

* Because colistin MIC was 256 mg / L, the combination of compound 1 with 2 and 4 fold colistin MIC was not tested due to the limiting solubility of colistin.

3. Commentary 3.1 Combination of Compound 1 with colistin and fosfomycin

  Colistin and fosfomycin, in combination with Compound 1, were tested against selected gram-negative bacteria producing different types of beta-lactamases; production of extended substrate specificity beta-lactamase (ESBL) is multidrug resistant Often associated with The increasing prevalence of multidrug resistant bacteria makes treatment options less, and the development of the use of new drug and / or antimicrobial combinations may solve this problem. Selected ESBL producing Gram negative bacteria (eg, CTX-M-15, VIM, NDM-1) were exposed to the combination of Compound 1 and colistin, and in some experiments, to the combination of Compound 1 and fosfomycin.

  It is clear from the data in section 2.2 that concentrations below the inhibitory concentrations of both colistin and fosfomycin did not sensitize the test strain to compound 1 as the MIC of compound 1 against the test strain did not decrease (see Section 2.2). Table 1A).

  In this first series of experiments, the checkerboard method was applied to the combination of Compound 1 and colistin, as colistin or fosfomycin below a single inhibitory concentration was combined with various concentrations of Compound 1 (see Section 2.4). This method will expose each test strain to two concentrations of the combination drug, namely Compound 1 and colistin. A commonly accepted parameter that exhibits synergy, additive effects, neutrality and antagonism is the FIC index. Synergism is defined as an FIC index less than 0.5. An additive or neutral effect is defined as an FIC index of 0.5 to 4 (additional> 0.5 to 1; neutral> 1 to 4). Antagonism is defined as an FIC index greater than 4 (the term relates to a method for measuring the susceptibility of bacteria to antimicrobials. Clinical microbiology and the European Association for Infectious Diseases (ESCMID) antimicrobial susceptibility test European Commission (EUCAST) EU CAST definitive document E. Def 1.2; Clin Microbiol Infect Dis 2000; 6: 503-508). The data summarized in Table 5 demonstrate that for all strains exposed to compound 1 + 0.5 or 2-fold colistin MIC, the FIC is between 0.5 and 2.5, thus demonstrating that it is neutral. .

  However, the interpretation of the FIC index is to be noted: For example, the average FIC index of 2.0 and 2.3 may be obtained by combining E. C. with Compound 1 in combination with 1 and 2 fold colistin MICs, respectively. Calculated for C. niger NRZ-00239. This means, for example, that in one of the experiments the colistin MIC is 1 mg / L and the MIC of compound 1 is 256 mg / L, whereby the FIC index of the 1 mg / L colistin + 256 mg / L compound 1 combination is neutral. Due to the fact that 0 (= (1 + 1) + (256/256)). However, exposure of this test strain to double colistin MIC + Compound 1 in a separate experiment results in a marked increase in sensitivity to Compound 1, reflecting the MIC value of <0.015 mg / L Compound 1. The FIC index of this combination of 2 mg / L colistin + 0.015 mg / L compound 1 is 2.00006 (= (2 + 1) + (0.015 / 256)), ie it is not different from above and also shows neutrality ing. The FIC index of the combination of 4 mg / L colistin + 0.015 mg / L compound 1 is 4 further. This example demonstrates that calculation of the FIC index is not consistent with the definition of synergy, addition, neutrality and antagonism. The Checkerboard method and FIC calculations are routinely used for the evaluation of combination studies, but this method has significant limitations: it is only data that quantitates repression, data that quantifies bactericidal activity It does not bring about, and the all-or-non reaction (growth or non-growth) alone does not bring about the stepwise response which quantifies the decrease of the viable count. Most importantly, the calculation of the FIC index incorrectly assumes that all combination partners show a linear concentration response (PIllai SK, Moellering RC, Eliopoulos GM. Antimicrobial combination. In: Antibiotics in Laboratory Medicin. Lorian V (Editor), Chapter 9, 5th Edition, 2005, Lippincrot Raven). Linear concentration-activity reactions have been demonstrated for colistin, fluoroquinolones and aminoglycosides, but not for β-lactams or compound 1. Thus, the FIC index is only a limited estimate for the characterization of the combined effects of Compound 1 with other agents. The MIC of Compound 1 in combination with 2 to 4 times the colistin MIC is from 256 mg / L to <0.015 mg / L for 5 test strains, 8 to 16 mg / L to <0.015 mg / L for E. coli ATCC 25922 strain The significant reduction to L and the simultaneous obtaining of an FIC index of 0.6 to 4.0 prove that the calculation of the FIC index is not a suitable method to explain these combined effects.

  This fact indicates that even if the FIC index shows neutrality, the death curve experiment shows low activity against gram negative bacteria as single substance Compound 1 is gram negative in the presence of 1 and 2 fold MIC colistin or fosfomycin of MIC This is corroborated by the findings that have been shown to exhibit antimicrobial activity against the test strain (see Section 5.3). Either Compound 1 + colistin or fosfomycin reduces viable counts and causes the test strain to disappear more rapidly from the system than either drug alone (Tables 3A, 3B and 4A, 4B). The finding that inhibitory concentrations of colistin or fosfomycin or concentrations above inhibitory concentration increase the activity of compound 1 against these gram negative indicator strains is indicated by MIC of compound 1 in checkerboard titration, for example, from 256 mg / L to <0.015 mg. It is also reflected by the fact that it has dropped to a low value of / L. Thus, inhibitory concentrations of colistin and concentrations above the inhibitory concentration reduce the MIC of Compound 1. It is known that polymyxin enhances the permeability of the outer membrane of Gram-negative bacteria (Vaara M., an agent that enhances the permeability of the outer membrane, Microbiol Rev 1992; 56 (3): 395-411), Thus, it can be explained by the fact that it lowers the MIC of other less active agents. However, the discovery of this test that the concentration of Compound 1 equivalent to 1 × MIC enhanced the bactericidal efficacy of colistin is unexpected.

  Thus, the combination of Compound 1 and colistin has obtained bactericidal activity which makes the antimicrobial treatment more effective. Furthermore, no antagonistic effects have been recorded, whereby the combination of Compound 1 and colistin significantly extends Compound 1's gram-positive antibacterial range to Gram-negative pathogens, including multidrug resistant strains that are difficult to treat.

3.2 Combination of Compound 1 with a combination drug Effect on Gram-negative bacteria:
The combination of Compound 1 clinically used in the treatment of infections due to gram negative pathogens with antimicrobials other than colistin or fosfomycin produces neutral results (see Section 2.2, Tables 1B and C), Compound 1 is It has been shown empirically that the treatment of the patient can possibly be combined with β-lactams, aminoglycosides, fluoroquinolones or tigecycline.

Effects on Gram-positive bacteria:
The combination of compound 1 with ampicillin or ceftriaxone at 0.5 times their MIC reduces on the one hand the MIC of compound 1 against the three MRSA indicator strains, but on the other hand against the MSSA test strain Not reduced (Section 2.2, Table 2A). This finding is surprising as the β-lactam target, penicillin binding protein 2 in MRSA strains was mutated to very low β-lactam affinity. The same is true for the combined effect of Compound 1 + Ceftriaxone against S. pneumoniae BAY 19397. Moreover, sensitive reference strains were not affected by this combination. It seems rather unlikely that exposure to compound 1 restores the affinity of the target for β-lactams. Thus, the findings in this test that the suppression of Ampicillin- or Ceftriaxone below concentrations in combination with Compound 1 acts synergistically against MRSA and β-lactam resistant Streptococcus and Enterococci are unexpected. Met. The combination of Compound 1 and .beta.-lactams restores the efficacy of .beta.-lactams in the treatment of methicillin- or penicillin-resistant staphylococci, streptococcus and enterococci.

  The combination of Compound 1 with vancomycin or daptomycin (Section 2.2, Table 2B) or tigecycline (Table 2C) produced neutral results.

  The combination of Compound 1 with either moxifloxacin or linezolid was very synergistic and reduced the MIC of Compound 1 to <0.000025 mg / L for most strains (Item 2.2, Table 2C) ). Thus, the combination of Compound 1 with either moxifloxacin or linezolid restores their activity against quinolone- or oxazolidinone-resistant bacteria and increases the activity of both combination partners against these difficult-to-treat gram-positive MDR isolates Let

From the above data the following can be concluded:
1. Colistin significantly enhances the activity of oxazolidinone-quinolone hybrids (e.g. compound 1) against gram-negative bacteria and extends the antibacterial range of oxazolidinone-quinolone hybrids (e.g. compound 1) to gram-negative bacteria including difficult-to-treat MDR strains.
2. Neutral or synergistic combination effects, oxazolidinone-quinolone hybrids (eg Compound 1) in combination with other commercially available antimicrobial agents used to treat Gram-negative pathogens to treat the initial experience of bacterial infections Can complement the main gram-positive range of oxazolidinone-quinolone hybrids (e.g. compound 1).
3. A high degree of synergy against MARS and MDR-Streptococcus pneumoniae or MDR-Enterococci was observed with the combination of oxazolidinone-quinolone hybrids (eg Compound 1) with β-lactams or moxifloxacin and linezolid, thus oxazolidinone- It enhances the activity of quinolone hybrids (eg Compound 1) and possibly restores the activity of β-lactams or moxifloxacin and linezolid.

Claims (3)

A medicament comprising a combination of i) at least one oxazolidinone-quinolone hybrid and ii) at least one further antibacterial compound different from the compound (i),
At least one oxazolidinone-quinolone hybrid comprising the following compounds:
7- (4- {4-[(5S) -5- (Acetylamino-methyl) -2-oxo-oxazolidin-3-yl] -2-fluoro-phenoxymethyl} -4-hydroxy-piperidin-1-yl ) -1-Cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid:

and
7- (4- {4-[(5S) -5- (Acetylamino-methyl) -2-oxo-oxazolidin-3-yl] -2-fluoro-phenoxymethyl} -4-phosphonoxy-piperidin-1-yl ) -1-Cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid:

Or a salt, solvate or hydrate thereof, and
The at least one further antimicrobial compound (ii) is
Colistin, fosfomycin, ampicillin, ceftriaxone, moxifloxacin and linezolid
A pharmaceutical agent for use in the treatment and / or prevention of a bacterial infection, selected from A pharmaceutical composition comprising the medicament according to claim 1 and optionally a carrier and / or diluent and / or adjuvant. i) at least one oxazolidinone of claim 1 - quinolone comprising different at least one further antimicrobial compound and hybrid and ii) A compound according to claim 1 (i), of bacterial infections treated and And / or kits of parts for use in prevention .